Prostate Protocol for Elevated PSA

The PSA Protocol by Jeffrey Dach MD

Jim is a 67 year old retired business man who had a PSA of 17.  His prostate biopsy was positive for prostate cancer, and Jim was then treated with radiation therapy with good results. After radiation treatment, the PSA was undetectable (Zero) indicating successful operation. However, about a year later, the PSA began to drift up reaching 3.2 indicating recurrent cancer. Jim was given the PAO-V and the PSA protocol (listed below) and the PSA rechecked 12 weeks later was again undetectable (zero). Note: The PSA is prostate specific antigen, a commonly used test marker for prostate cancer.

Sam is a 63 year old former professional athlete who had been taking testosterone injections for many years during which time the PSA was always below 4.0. However, on two occasions, the PSA gradually rose to the 9.2 area. On both occasions, Sam was given the PSA protocol (listed below). Follow up PSA 12 weeks later showed decline back to under 4.0.

Header Photo: Dr. Mirko Beljanski, courtesy of wikimedia commons. Author Chantal.nsi
Creative Commons Attribution-Share Alike 3.0 Unported license.

When serial PSA measurements are done on males using testosterone, one may occasionally find elevated PSA, gradually drifting up over time to eventually reach the4.0 level which is the level which triggers prostate biopsy by the local urologist searching for underlying prostate cancer. However, one must keep in mind two other causes of elevated PSA, prostatitis (acute or chronic) and BPH (benign prostatic hypertrophy). These are also fairly common. Prostatitis can be treated with antibiotics and synergistic supplements such as a proteolytic enzyme, nattokinase, after which one may frequently find the PSA has returned to normal range, thereby avoiding the dreaded prostate biopsy. The PSA is not only a cancer marker, it is also a marker for prostate volume, and will go up as the prostate enlarges with BPH. We typically see the PSA go up slightly when starting testosterone injections, and see PSA go down slightly when starting testosterone blocking drugs such as finasteride, dutasteride (5-alpha reductase inhibitors). This is due to the effect of these drugs on prostate volume.

If the cause of the elevated PSA is prostatitis, antibiotics such as minocycline are usually effective, and the PSA will promptly decline. Nattokinase is a proteolytic enzyme which dissolves biofilm, thus assisting the minocycline penetration into pockets of infection within the prostate. (82-85)

If the cause is BPH, the PSA may be above 4.0, but usually remains stable, thus indicating the PSA is a result of increased prostate volume from BPH, and not rising as one would find in a growing cancer.

If the cause of the elevated PSA is low grade prostate cancer, the PSA may gradually drift up in a very slow manner over months or years. In the more aggressive prostate cancers, the PSA will go up much faster, and reach very high levels in shorter periods of time. Minocycline is not only an antibiotic. It is also anti-inflammatory and anti-cancer, thus representing a good treatment for underlying low grade prostate cancers. On follow up PSA testing after treatment with minocycline, one frequently finds the PSA declining back into normal range. The other supplements also have anti-cancer activity and synergize with minocycline. For patients who fail to respond or only partially respond to the PSA protocol, these patients have a more aggressive cell type of prostate cancer and will need conventional treatment with radiation therapy or prostatectomy. This will be obvious, as the PSA will fail to respond to the PSA protocol and continue to rise. Since the vast majority of prostate cancer cases are indolent slow growing cell types, the PSA protocol is a useful addition to our armamentarium, and when the PSA declines back into the normal range, the patient is spared the dreaded prostate biopsy. In this article we will go over each component of the PSA protocol along with the supportive medical literature. (92)

Minocycline

Minocyline is an old tetracycline derived antibiotic, FDA approved in 2002. Not only is minocycline an excellent antibiotic, it is also anti-inflammatory, anti-cancer and anti-viral. Anti-cancer properties extend to many other cancer cell types. Minocycline has also been used to treat sarcoidosis, a granulomatous disease of unknown etiology. As we all know, antibiotics will disrupt the microbiome of the gut, the friendly bacteria, thus explaining the importance of taking probiotics to restore the microbiome. (13) (93-140)

Pao-V by Beljanski

Pao-V was developed by Dr. Mirko Beljanski (27 March 1923 – 27 October 1998), a Serbian, French microbiologist who discovered reverse transcriptase at the Pasteur Institute in Paris in 1971. During his career, Dr. Mirko Beljanski developed several anti-cancer products based on extracts from plants found in the Amazon rain forest. After his death in 1998, his daughter, Sylvie, carried on her father’s work with the Beljanski foundation which sponsors annual cancer meetings and offers her father’s anti-cancer extracts to the public. The Pao extract is derived from the bark of the Pao Pereira tree in the Amazon rain forest used in local tribal medicine. Pao-V is useful for BPH (benign prostatic hyperplasia) and is active against prostate cancer, and other cancers as well. (1-12)

Iodine

Iodine is used to fortify iodized salt, and available as Lugol’s Solution as an over-the-counter iodine supplement.  An iodine tablet developed by Guy Abraham MD is a popular over the counter supplement containing 10 percent potassium iodide and 5 percent molecular iodine, similar to Lugol’s solution. A topical antiseptic cleaning agent called Povidone Iodine is available at the local drug store. Iodine has anti-cancer activity by virtue of iodolactone formation, and is active against prostate, breast and other cancers which take up iodine. Another anti-cancer mechanism is the ability of iodine to divert estrogen metabolism towards the 2-methoxy-estradiol metabolite, which in itself has significant anti-cancer activity. Iodine also diverts estrogen metabolism away from the carcinogenic quinone estrogen metabolites. For more on estrogen metabolism, see: Estrogen Metabolism, Iodine and 2MEO. Note:  Both Dr. George Flechas and Dr. David Brownstein worked closely with Dr. Abraham for many years on the Iodine Project. Dr. Abraham passed away in 2013. (14-24) (175-180)

 

Soy Iso-Flavones

Various phyto-estrogens called soy isoflavones, Apigenin, Daidzein, Genistein are ER-beta ligands have anti-cancer activity. Reserveratrol reduces ER-alpha and increases ER-beta expression, and therefore useful against prostate cancer. The DHT metabolite 3β-Adiol activates ER-beta, and has anti-cancer activity. (24-27) (63-67)

Milk Thistle, Silybin, silymarin for prostate cancer

The main extract of milk thistle is called Silybin or silymarin, commonly used for liver support. Silybin has excellent anticancer activity, and has been studied in prostate cancer animal models. Silybin (Silibinin) inhibits the growth of human advanced prostate cancer xenografts in a mouse model. In 2024, Dr. Pantha Prodip Ray reviewed the role of silibinin in cancer treatment writing:

Silibinin inhibits the growth of human, mouse, and rat prostate cancer cells, as well as the formation of human prostate tumor xenografts in nude mice. It has also shown suppression of prostate cancer growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. Silibinin has entered phase I/II clinical trials in prostate cancer patients… (28-39)

Silibinin is also useful in treatment of BPH. (40-41)

I3C/DIM

In a previous newsletter, Estrogen Metabolism, Iodine, and 2MEO Part Three, the beneficial effect of I3C/DIM on estrogen metabolism was discussed. DIM (diindolylmethane) is also useful for prostate cancer prevention. I3C/DIM downregulates ER-alpha and induces CYP1A1 which leads to increased anti-cancer metabolite 2 methoxyestradiol. DIM also makes ER-beta more active by increasing binding of ER-beta to estrogen response elements. (42) (141-149)

Pterostilbene for Prostate cancer

Pterostilbene is a methylated version of resveratrol, considered more biologically active and potent as an anti-cancer agent. Pterostilbene has been extensively studied as an anti cancer agent in various cancer cell types using in-vitro and in-vivo models. (68-81)

Sulforaphane from Broccoli Sprouts

In 2015, Dr. Bernard G Cipolla studied the use of sulforaphane for men with biochemcial recurrence after radical prostatectomy. After surgical treatment for prostate cancer, the PSA should be zero, indicating successful operation. After the operation, the PSA should stay at zero. If the PSA starts to rise post-operatively, this is called biochemical recurrence, indicating regrowth of prostate cancer. Dr. Cippola found 60 mg/day of sulforaphane useful for reducing PSA values in males with “biochemical recurrence”, writing:

Treatment comprised daily oral administration of 60 mg of a stabilized free SF [sulforaphane] for 6 months (M0 to M6) followed by 2 months without treatment (M6 to M8). The study was designed to detect a 0.012 log (ng/ml)/month decrease in the log PSA slope in the SF group from M0 to M6. The primary end-point was not reached. For secondary end-points, median log PSA slopes were consistently lower in SF-treated men. Mean changes in PSA levels between M6 and M0 were significantly lower in the SF group (+0.099 ± 0.341 ng/ml) compared with placebo (+0.620 ± 1.417 ng/ml; p = 0.0433). PSA doubling time was 86% longer in the SF than in the placebo group (28.9 and 15.5 months, respectively). PSA increases >20% at M6 were significantly greater in the placebo group (71.8%) than in the SF group (44.4%); p=0.0163. Compliance and tolerance were very good. SF effects were prominent within 3 months of intervention (M3 to M6). After treatment, PSA slopes from M6 to M8 remained the same in the two arms.(91) (86-91)

Sulforaphane is also “highly beneficial” in preventing gastric ulcerative disease by inhibiting the growth of Helicobacter pylori. (90)

There are many other plant substances with antic-cancer activity useful for rising PSA. Here are a few more of these: Thymoquinone (44-45),  Tocotrienol Vitamin E (46-62)

ER-alpha and ER-beta Estrogen Receptors

Prostate cancer has many similarities to breast cancer. For example, they are both driven by ER-alpha estrogen receptor signalling, and both inhibited by ER-beta estrogen receptor signalling. ER alpha is the proliferative receptor, while ER-beta is the tumor suppressor receptor. This also holds true for many other cancer cell types.For example, in the two most common skin cancers, squamous cell and basal cell, endogenous estrogens play a critical role in preventing these cancers. (170-174)

Mouse Models of Skin Cancer, ER-alpha and ER-beta

In 2009, Dr. Mancuso studied mouse models of skin cancer finding ER-alpha caused malignant progression wheras ER-beta was protective and preventive of skin cancer. Rendering the animal estrogen deficient in two separate mouse models increased ER-alpha activity and decreased ER-beta expression. Reduced ER-beta exoression and unrestrained ER-alpha activity increased transcription of the Cyclin D1 Oncogene, associated with malignant progression, writing:

To shed light on potential mechanisms involved in estrogen modulation of skin tumor progression, we examined ER protein levels in benign skin papillomas from the different Car-S groups. Immunoblots of papilloma extracts showed significantly increased expression of ER-alpha and downregulation of ER-beta in tumors from OVX [ovariectomy] relative to CN tumors [control benighn papillomas], suggesting… a correlation of decreased ER-beta expression with increased malignant progression of initially benign papillomas in ovariectomized Car-S mice…In the presence of estrogen, cyclin D1 is one important target gene through which estrogen-complexed ER-alpha mediates its proliferative action, whereas estrogen-complexed ER-beta represses cyclin D1 gene transcription and blocks ER-alpha-mediated induction when both receptors are present…In the absence of estrogen, however, cyclin D1 is able to bind to and activate transcription mediated by ER-alpha. Significantly, we detected cyclin D1 upregulation in tumors from OVX relative to CN mice. ..This hypothesis is supported by the higher proliferation rate observed in papillomas from OVX compared with intact CN mice, a finding also observed in ER-positive breast cancer, where high cyclin D1 expression correlates with high Ki67 expression…In summary, our study shows for the first time a protective role of endogenous estrogen against basal and squamous skin tumorigenesis caused by physical or chemical agents in independent mouse models Finally, our study suggests that reciprocal expression of ERalpha and ERbeta may be associated with estrogen-mediated modulation of squamous epithelial carcinogenesis, with a key role played by cyclin D1. (181)

What Causes Prostate Cancer ?

Both prostate and breast cancer are thought to be caused by downstream estrogen metabolites, the catechol estrogen quinones. Most of the work on carcinogenic estrogen metabolites has been done by Dr. Ercole Cavalieri who devoted her career to studying carcinogenic catechol estrogen quinones as a driving force for both breast and prostate cancer. (27)

===================
PSA Protocol
===================

1) Minocycline 100 mg PO BID x 8 weeks, #112 caps – Prescription will be sent your pharmacy by your physician.

2) Pao-V by Beljanski® – Pao V® Dietary Supplement – Pao Pereira Extract – 100 Capsules, one cap twice a day in between meals . Buy two bottles. Link to Buy on Amazon:

The items listed below can be ordered through Fullscript, an online vitamin catalog:

3) Pterostilbene Jarrow formulas Pteropure 50 mg caps PO 2 caps twice a day/ 4 bottles
4) Sulforaphane BroccoMax Jarrow Two caps 30 min before meal twice a day / 2 bottles
5) Probiotics – Dr. Ohhira’s Probiotic Professional Formula-Essential Formulas, 60 capsules/ take one a day.
6) Optimox® Iodoral® 12.5mg 90 Tablets / take one a day
7) DIM-plus, Nature’s Way, 60 capsules / Take one capsule twice daily with food.
8) Nattokinase 100 mg NSK-SD® Allergy Research Group
9) Silymarin 500 mg capsules Pure Encapsulations

To Order on Fullscript Click Here
Note: if the above link does not work for you, then call my office (954-792-4663) and they will walk you through it.

====================================

Links to Related Articles:

Estrogen Metabolism, Iodine, and 2MEO

All Bioidentical Hormone Articles

PSA Screening for Prostate Cancer, the Failed Medical Experiment

Testosterone, PSA and Prostate Cancer Myths and Misconceptions

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663

References

PAO V (Beljanski) for Prostate Cancer

1) Chang, Cunjie, et al. “Pao pereira extract suppresses castration-resistant prostate cancer cell growth, survival, and invasion through inhibition of NFκB signaling.” Integrative Cancer Therapies 13.3 (2014): 249-258.

Pao extract, derived from bark of Amazonian tree Pao Pereira, is commonly used in South American medicine. A recent study showed that Pao extract repressed androgen-dependent LNCaP prostate cancer cell growth. We hypothesize that Pao extract asserts its anticancer effects on metastatic castration-resistant prostate cancer (CRPC) cells. Pao extract suppressed CRPC PC3 cell growth in a dose- and time-dependent manner, through induction of apoptosis and cell cycle arrest. Pao extract treatment induced cell cycle inhibitors, p21 and p27, and repressed PCNA, Cyclin A and Cyclin D1. Furthermore, Pao extract also induced the upregulation of pro-apoptotic Bax, reduction of anti-apoptotic Bcl-2, Bcl-xL, and XIAP expression, which were associated with the cleavage of PARP protein. Moreover, Pao extract treatment blocked PC3 cell migration and invasion. Mechanistically, Pao extract suppressed phosphorylation levels of AKT and NFκB/p65, NFκB DNA binding activity, and luciferase reporter activity. Pao inhibited TNFα-induced relocation of NFκB/p65 to the nucleus, NFκB/p65 transcription activity, and MMP9 activity as shown by zymography. Consistently, NFκB/p65 downstream targets involved in proliferation (Cyclin D1), survival (Bcl-2, Bcl-xL, and XIAP), and metastasis (VEGFa, MMP9, and GROα/CXCL1) were also downregulated by Pao extract. Finally, forced expression of NFκB/p65 reversed the growth inhibitory effect of Pao extract. Overall, Pao extract induced cell growth arrest, apoptosis, partially through inhibiting NFκB activation in prostate cancer cells. These data suggest that Pao extract may be beneficial for protection against CRPC.

2) Liu, Jiakuan, et al. “Pao pereira extract attenuates testosterone-induced benign prostatic hyperplasia in rats by inhibiting 5α-reductase.” Scientific reports 9.1 (2019): 19703.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in the urinary system of elderly men. Pao extract is an herbal preparation of the bark of the Amazon rainforest tree Pao Pereira (Geissospermum vellosii), which was reported to inhibit prostate cancer cell proliferation. Herein we investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced the prostate enlargement, compared with the sham operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights and sperm number of rats, compared with the control group. Furthermore, Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. Moreover, Pao extract and its active component, flavopereirine, induced cytotoxicity on human prostate epithelial RWPE-1 cells in a dose- and time- dependent manner with G2/M arrest. Consistently, Pao extract and flavopereirine suppressed the expression levels of SRD5A1, AR and PSA, respectively. Together, these data demonstrated that Pao extract suppresses testosterone-induced BPH development through inhibiting AR activity and expression, and suggested that Pao extract may be a promising and relative safe agent for BPH.

3) Bemis, Debra L., et al. “β-Carboline alkaloid–enriched extract from the Amazonian rain forest tree pao Pereira suppresses prostate cancer cells.” Journal of the Society for Integrative Oncology 7.2 (2009): 59.

Bark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in α-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, we preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice. However, we observed a striking U-shaped dose-response curve in which the highest dose tested (50 mg/kg/d) was much less effective in inducing tumor cell apoptosis and in reducing tumor cell proliferation and xenograft growth compared with lower doses (10 or 20 mg/kg/d). Although this study supports the idea that a pao pereira bark extract has activity against human prostate cancer, our in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.

4) Yu, J., J. Drisko, and Q. Chen. “P01. 38. Anti-cancer activity of extracts from Rauwolfia vomitoria and Pao Pereira.” BMC Complementary and Alternative Medicine 12 (2012): 1-1.

Five pancreatic cancer and three ovarian cancer cell lines were tested that exhibited different resistance to the 1st line chemo-drug gemcitabine (Gem, for pancreatic cancer), and carboplatin (Cp, for ovarian cancer). Chou-Talalay’s method was used to evaluate drug combination.

To test whether the treatments of Rau or Pao could enhance the cells’ sensitivities to chemo-drugs, we combined either Rau or Pao with gemcitabine to treat pancreatic cancer cells, and with carboplatin to treat ovarian cancer cells. The combination treatments took Chou-Talalay’s constant ratio design, with molar ratio set to IC_50extract: IC_50Chemo. The combined-treatments significantly enhanced cell death in cancer cells which were strongly resistant to gemcitabine or carboplatin (p<0.05). The results showed a left-shift in the dose-response curves of the combination treatments compared to the corresponding curves with either Gem or Cp alone in all tested cancer cells. Combination indices (CIs) were <1, indicating synergistic effects.

==================================

Pao V for Pancreatic Cancer

5) Yu, JuN, Jeanne Drisko, and Qi Chen. “Inhibition of pancreatic cancer and potentiation of gemcitabine effects by the extract of Pao Pereira.” Oncology reports 30.1 (2013): 149-156.

6) Dong, Ruochen, Ping Chen, and Qi Chen. “Extract of the medicinal plant Pao Pereira inhibits pancreatic cancer stem-like cell in vitro and in vivo.” Integrative Cancer Therapies 17.4 (2018): 1204-1215.

Pao V for Ovarian Cancer

7) Chen, Ping, Ruochen Dong, and Qi Chen. “Extracts of the medicinal plants pao pereira and rauwolfia vomitoria inhibit ovarian cancer stem cells in vitro.” Integrative Cancer Therapies 21 (2022): 15347354221123019.

8) Yu, Jun, and Qi Chen. “The plant extract of Pao pereira potentiates carboplatin effects against ovarian cancer.” Pharmaceutical Biology 52.1 (2014): 36-43.

===================================

Buy Pao- V

9) https://www.beljanski.org/pao-pereira/research-pao-pereira/
Publications on Pao Pereira

10) Link to buy on Amazon; Beljanski® – Pao V® Dietary Supplement – Pao Pereira Extract – 100 Capsules

11) Buy on Maison Beljanski Pao V® ( 59 ) $87.00

Pao V® is a dietary supplement extracted from the bark of Pao pereira according to extraction and purification methods developed and patented by Dr. Mirko Beljanski (under the name of PB100). Each stage of the production of this exclusive extract is subject to rigorous controls.

Even though they lived in a naturally preserved environment, for centuries South American Indian tribes have used the bark of Pao pereira (Geissospermum Vellosii), a tree from the Amazonian rain forest, particularly when additional support to the immune system was needed.1

12) https://www.amazon.com/Prostabel%C2%AE-Beljanski-Product%C2%AE-Supports-Prostate/dp/B004QOP0RY
Beljanski® Products – Prostabel® – Supports Prostate and Urinary Health – 100 Capsules

========================================================

Repurposed Drugs 2023 Prostate Cancer –

13) Lourenço, Tânia, and Nuno Vale. “Pharmacological efficacy of repurposing drugs in the treatment of prostate cancer.” International Journal of Molecular Sciences 24.4 (2023): 4154.

Ivermectin, which is also in the anthelmintic group, acts on PC via cell cycle arrest, inducing apoptosis and a decrease in androgen receptor expression, and these are associated with a Proliferating Cell Nuclear Antigen (PCNA) and a decrease in cyclins D and E and an increase in p21. Ivermectin also acts on the FOXA1 protein and Ku70/Ku80 heterodimer, inhibiting them and blocking androgen receptor signaling, E2F1 expression and DNA damage repair, resulting in cell cycle arrest [25,26].

In addition to this, ivermectin causes a synergistic effect in combination with docetaxel, reduces cancer cells’ viability, causing their apoptosis and, consequently, decreases the tumor size. Although the synergic mechanism of these two drugs is still not well understood, it may be related to the inhibition of multidrug resistance (MDR) caused by ivermectin [25].

Minocycline is a tetracycline derivative that inhibits pro-inflammatory cytokines and metalloproteinases that are associated with tumor invasion and metastasis development, and, for this reason, this drug is in clinical trials to be repurposed for PC treatment, in which it has been found that minocycline inhibits LYN kinase and STAT3, suppresses EMT and consequently blocks metastases [2,34]. On the other hand, the chemical modification of tetracyclines (CMT-3) by activating caspase-3 and caspase-9 and by inhibiting metalloproteinases induces apoptosis in PC cells [2,5].

======================================

Iodine for Prostate Cancer

Iodine anti-inflammatory in Prostate- MICE

14) Anguiano, Brenda, et al. “Protective effects of iodine on rat prostate inflammation induced by sex hormones and on the DU145 prostate cancer cell line treated with TNF.” Molecular and Cellular Endocrinology 572 (2023): 111957.

• Iodine (I2) and testosterone have anti-inflammatory effects in rat prostate.
  •I2 reduces cell viability and interleukin 6 secretion in DU145 cells.
  •I2 and tumor necrosis factor have an additive effect on loss of cell viability.
  •I2 antagonizes the tumor necrosis factor-induced interleukin 6 secretion.

In-vivo xenograft study mice, Iodine anticancer effects Prostate Cancer

15) Aranda, Nuri, et al. “Uptake and Antitumoral Effects of Iodine and 6-Iodolactone in Differentiated and Undifferentiated Human Prostate Cancer Cell Lines.” Prostate 73 (2013): 31-41.

16) Aranda, Nuri, et al. “Uptake and antitumoral effects of iodine and 6‐iodolactone in differentiated and undifferentiated human prostate cancer cell lines.” The Prostate 73.1 (2013): 31-41.

METHODS. Non-cancerous (RWPE-1) and cancerous (LNCaP, DU-145) cells, as well as
nude mice xenotransplanted with DU-145 cells were used as cancer models. Iodine uptake was analyzed with radioactive tracers, transporter expression by qRT-PCR, cell proliferation by blue trypan, apoptosis by enzyme immunoassay or fluorescence, BAX and BCL-2 by western-blot, and caspsase 3 by enzymatic assay.

RESULTS. All three cell lines take up both forms of iodine. In RWPE-1 cells, I uptake depends on the Na/I symporter (NIS), whereas it was independent of NIS in LNCaP and DU-145 cells. Antiproliferative effects of iodine and 6-IL were dose and time dependent; RWPE-1 was most sensitive to I and 6-IL, whereas LNCaP was more sensitive to I2. In the three cell lines both forms of iodine activated the intrinsic apoptotic pathway (increasing the BAX/BCL-2 index and caspases). Iodine supplementation impaired growth of the DU-145 tumor in nude mice.
CONCLUSION. Normal and cancerous prostate cells can take up iodine, and depending on
the chemical form, it exerts antiproliferative and apoptotic effects both in vitro and in vivo.

I2 for breast cancer and prostate cancer,
Decreases PSA levels

17) Aceves, Carmen, et al. “Molecular iodine has extrathyroidal effects as an antioxidant, differentiator, and immunomodulator.” International journal of molecular sciences 22.3 (2021): 1228.

We review the literature that shows that molecular iodine (I₂) exerts multiple and complex actions on the organs that capture it, not including its effects as part of thyroid hormones. This chemical form of iodine is internalized by a facilitated diffusion system that is evolutionary conserved, and its effects appear to be mediated by a variety of mechanisms and pathways. As an oxidized component, it directly neutralizes free radicals, induces the expression of type II antioxidant enzymes, or inactivates proinflammatory pathways. In neoplastic cells, I₂ generates iodolipids with nuclear actions that include the activation of apoptotic pathways and the inhibition of markers related to stem cell maintenance, chemoresistance, and survival. Recently, I2 has been postulated as an immune modulator that depending on the cellular context, can function as an inhibitor or activator of immune responses. We propose that the intake of molecular iodine is increased in adults to at least 1 mg/day in specific pathologies to obtain the potential extrathyroid benefits described in this review.

Dose-response studies in humans have demonstrated that I₂ at concentrations of 1 to 6 mg/day exhibited significant beneficial actions in benign pathologies like fibrocystic breast disease [21,22], prostatic hyperplasia [23] and polycystic ovaries (unpublished results). The treatments in these studies lasted from five weeks up to two years and did not have any side effects at these concentrations. Some of the dose-response studies also analyzed the highest concentration of iodine (9 and 12 mg/day) and showed the same benefits but accompanied, in some cases, by transient hypothyroidism and/or minor side effects like headache, sinusitis, acne or diarrhea. These effects disappeared when the high dose of supplemental iodine was suspended [24].

Although the main uptake of iodine takes place in the thyroid, many other organs take it up (Figure 1), including the salivary glands, gastric mucosa, lactating mammary gland, nervous system, choroid plexus, ciliary body of the eye, lacrimal gland, thymus, skin, placenta, ovary, uterus, prostate, and pancreas, and they can maintain or lose this ability in pathological conditions [1]. The I⁻ transport system in many of these extrathyroidal tissues involves the expression of the sodium iodide symporter (NIS) and/or the anion exchanger Pendrin (PDS/SLC26A4).

Indeed, we demonstrated that the thyroid, mammary gland, and prostate can accumulate both types of iodine, which are captured by different mechanisms. The thyroid, lactating mammary gland, and prostate exhibit a significant uptake of I⁻, which is internalized by NIS (inhibited by KClO₄).

Iodine deficiency in rats is accompanied by ductal hyperplasia and perilobular fibrosis in the virgin mammary glands, and the supplement of I₂ but not I⁻ reverts these alterations [14]. Similarly, the supplement of I₂ (3–6 mg/day) in patients with fibrocystic breast disease is accompanied by remission of symptoms, as well as significant anti-inflammatory effects [21,22]. Our group has found similar benefits in benign prostatic hyperplasia (BPH) in preclinical and clinical models [36]. In human patients with early BPH (Grade I and II), the supplement of 5 mg/day of Lugol’s solution (mix 1:3; I₂:KI) for 8 months decreased the prostate-specific antigen (PSA) circulating levels and improved the urinary flow and symptoms scale [23].

Several groups have postulated that iodine may have an ancestral antioxidant function in all the cells that concentrate it, from primitive algae to the most recent vertebrates [3,4].

Antineoplastic action of the I2 supplement without harmful effects on the thyroid has also been observed in mammary and prostatic pathologies in preclinical (rodents and canines) and clinical protocols [25,26,27,28].

In human patients with early BPH (Grade I and II), the supplement of 5 mg/day of Lugol’s solution (mix 1:3; I2:KI) for 8 months decreased the prostate-specific antigen (PSA) circulating levels and improved the urinary flow and symptoms scale [23].

23. Anguiano, B., et al. “Therapeutic effect of iodine on human benign prostatic hyperplasia.” Proceedings of the 14th International Thyroid Congress, Paris, France. 2010.

These studies agree with epidemiological data that associate the low incidence of breast and prostate pathologies with the moderately high dietary intake of iodine in Asian countries [3,4,37].

Iodine for Prostate Cancer

18) Iodine and Cancer A summary of the evidence to date By Tina Kaczor, ND, FABNO

19) Olvera-Caltzontzin, Paloma, et al. “Iodine uptake and prostate cancer in the TRAMP mouse model.” Molecular Medicine 19.1 (2013): 409.

Iodine supplementation exerts antitumor effects in several types of cancer. Iodide (I-) and iodine (I2) reduce cell proliferation and induce apoptosis in human prostate cancer cells (LNCaP and DU-145). Both chemical species decrease tumor growth in athymic mice xenografted with DU-145 cells. The aim of this study was to analyze the uptake and effects of iodine in a preclinical model of prostate cancer (transgenic adenocarcinoma of the mouse prostate [TRAMP] mice/SV40-TAG antigens), which develops cancer by 12 wks of age. 125I- and 125I2 uptake was analyzed in prostates from wild-type and TRAMP mice of 12 and 24 wks in the presence of perchlorate (inhibitor of the Na+/I- symporter [NIS]). NIS expression was quantified by quantitative polymerase chain reaction (qPCR). Mice (6 wks old) were supplemented with 0.125 mg I- plus 0.062 mg I2/mouse/day for 12 or 24 wks. The weight of the genitourinary tract (GUT), the number of acini with lesions, cell proliferation (levels of proliferating cell nuclear antigen [PCNA] by immunohistochemistry), p53 and p21 expression (by qPCR) and apoptosis (relative amount of nucleosomes by enzyme-linked immunosorbent assay) were evaluated. In both age-groups, normal and tumoral prostates take up both forms of iodine, but only I- uptake was blocked by perchlorate. Iodine supplementation prevented the overexpression of NIS in the TRAMP mice, but had no effect on the GUT weight, cell phenotype, proliferation or apoptosis. In TRAMP mice, iodine increased p53 expression but had no effect on p21 (a p53-dependent gene). Our data corroborate NIS involvement in I- uptake and support the notion that another transporter mediates I2 uptake. Iodine did not prevent cancer progression. This result could be explained by a strong inactivation of the p53 pathway by TAG antigens.

There is evidence that prostate epithelium is an iodine-responsive target. In several species, NIS mRNA was detected in normal and cancerous prostate (21�23). In humans, NIS protein is present in 50�70% of adenocarcinomas (24). With regard to the effects of iodine, in vitro studies show that LNCaP and DU-145 prostate cancer cells take up both I- and I2, and treatment with either chemical species reduces cell proliferation and induces apoptosis (Bax capsases). Consistent with these results, supplementation in nude mice with both chemical species consistently reduces tumor growth of DU-145 xenografts (25). The aims of this study were to analyze the uptake and potential antineoplasic effects of a mixture of iodine and iodide in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, a preclinical model of prostate cancer.

20) Cann SA, Qiu Z, and van Netten C. A Prospective Study of Iodine Status, Thyroid Function, and Prostate Cancer Risk: Follow-up of the First National Health and Nutrition Examination Survey. Nutrition and Cancer. 2007. 58(1): 28-34. Full text if it is still up.

21) TJA Key, et al. A case-control study of diet and prostate cancer. British Journal of Cancer. 1997. 76(5): 678-687. Full text.

Iodine Treats Breast cancer

22) Mendieta, Irasema, et al. “Molecular iodine exerts antineoplastic effects by diminishing proliferation and invasive potential and activating the immune response in mammary cancer xenografts.” BMC cancer 19.1 (2019): 261.

======================================

2-MEO and Prostate Cancer

23) Kumar, Addanki P., Gretchen E. Garcia, and Thomas J. Slaga. “2‐methoxyestradiol blocks cell‐cycle progression at G2/M phase and inhibits growth of human prostate cancer cells.” Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center 31.3 (2001): 111-124.

==========================================

2MEO and Estrogens and Prostate Cancer

24) Figueira, Marília I., et al. “The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on Phytoestrogens.” Biomedicines 12.8 (2024): 1636.

It has been widely accepted that ERα and ERβ drive differential responses in PCa [27,28], with ERα associated with protumorigenic effects, whereas ERβ has been implicated in the antitumorigenic actions of estrogens [29,30,31]. The complexity of estrogen actions in PCa increases considering GPER, as this membrane receptor has been shown to trigger both tumor growth and tumor regression effects [18]. Overall, despite disclosing the mechanism of action and the panoply of anticancer actions, research efforts have not found safe approaches for re-introducing estrogens in PCa therapy [32].

Estrogens in Prostate Cancer Therapy

3.1. Old-Times and Withdrawal

The use of estrogens in PCa therapy goes back to the 1940s. The pioneering work of Huggins and Hodges, which established PCa as a hormone-sensitive cancer, confirming its inhibited growth by the suppression of androgens levels or estrogen administration [6,7], has provided the foundations for the use of hormone therapy.

Estrogens were used in PCa treatment for several years, with the synthetic estrogen DES being a low-cost effective therapy for delaying the progression of metastatic PCa [7,8,9,10,11,12]. In the 1960s and 1970s, the Veterans Administration Cooperative Urological Research Group performed various randomized trials to evaluate the effectiveness of estrogenic therapies for PCa treatment, alone or in combination with orchiectomy [95]. This and other studies observed that estrogen therapy was able to delay the progression of PCa, accomplishing clinical responses in up to 80% of patients [8,9,10]. However, clinical trials also highlighted the adverse effects of hormone therapy, namely its hazardous effects at the cardiovascular level, with associated lethality [8]. A notorious increased risk of cardiovascular toxicity was found in up to 35% of patients receiving estrogen therapy, and thromboembolism was experienced by 15% [3,4,5].

ER-Alpha Drive Prostate Cancer

Yu and colleagues observed that E2 induced the neoplastic transformation of rat prostate epithelial cells [13]. These transformed cells displayed an increased expression of several putative PCa stem cell markers as well as changes in the expression of hormone receptors, namely, increased levels of ERα and the decreased expression of ERβ and AR [13,151], which indicates a change in the hormone-responsiveness accompanying tumor development. Moreover, these findings support the driven role of ERα in prostate carcinogenesis. Low doses of E2 also increased tumor growth in DU145 and PC3 cell xenograft models [14]. However, the carcinogenic effects of estrogens have mainly been demonstrated by their association with testosterone (Table 3). Rat treatment with E2, in addition to testosterone, promoted tumor development, causing the formation of DNA adducts, oxidative DNA damage, and lipid peroxidation [160]. In mice, the pathologic areas induced by the testosterone plus E2 treatment showed an increased number of PCNA-positive proliferating cells [144]. Moreover, the addition of E2 was shown to shift the incidence of prostate tumors to 100% compared only to an incidence of 35–40% when testosterone was given alone [159]. These findings implicate estrogens in prostate carcinogenesis and indicate that the known effects of androgens driving cancer may depend on testosterone aromatization to E2, which has been demonstrated in animal models.

Aromatase Knockout Mice, ER-Alpha knockout mice

Aromatase knockout mice, unable to synthesize E2, displayed a reduced incidence of PCa compared with wild-type animals in response to testosterone administration [144]. This study also showed that the presence of a functional ERα is decisive for tumor development. E2 plus testosterone treatment was ineffective, inducing PCa in ERα knockout mice, whereas ERβ knockout animals displayed a biochemical and histological pattern of carcinogenesis similar to their wild-type counterparts [144].

2-methoxyestradiol in Prostate Cancer

Additionally, the antitumor role of the endogenous metabolite of E2, 2-methoxyestradiol (2-ME2), has been widely studied in PCa. Kumar et al. [207] were the first to demonstrate that 2-ME2 inhibits the growth of non-neoplastic prostate epithelial cells. This growth inhibitory effect and the reduction in cell proliferation by 2-ME2 were also observed in a variety of both androgen-sensitive and CRPC cell line models (Figure 3 and Supplementary Table S1) [207,208,209,210,211,212]. Unsurprisingly, 2-ME2 has been highly associated with apoptosis induction in PCa (Supplementary Table S1) [207,208,209,210,211,213,214,215,216,217,218

In vivo findings in rats and mice further supported the enormous quantity of in vitro evidence of the antitumorigenic role of 2-ME2. Copenhagen X Fisher F1 male rats transplanted with Dunning R3327-PAP prostate tumors treated with 12.5 mg/kg/day of 2-ME2 showed reduced tumor growth accompanied by increased apoptosis [213]. Accordingly, in both androgen-sensitive or CRPC xenograft mice models, 2-ME2 treatment could reduce tumor growth and augment apoptosis (Supplementary Table S1) [208,210,211,218,219,220,221].

Additionally, in the TRAMP mice model, in which tumor development resembles the progression of human PCa (hyperplasia, 8–12 weeks; neoplasia, 15–18 weeks; metastasis, 24 weeks), the effect of 2-ME2 treatment in reducing tumor growth was confirmed. The administration of 2-ME2 had an important role during the various stages of PCa, reducing prostate weight, malignant transformation, and neoplastic progression as well as promoting tumor regression [210,218,221]. Moreover, these effects were accompanied by a reduction in testosterone [221] and PSA levels [210]. However, Ganapathy and colleagues [218] observed a reduction in apoptosis in TRAMP mice treated with 2-ME2, which was suggested to be related to restoring normal tissue architecture.

DHT metabolite 3β-Adiol – Activates ER-Beta
Anti-Prostate Cancer Activity

Some years ago, it was demonstrated that the DHT metabolites, 5α-androstane-3α,17β-diol (3α-diol) and 5α-androstane-3β,17β-diol (3β-Adiol), have estrogenic activities via the activation of ERβ [222,223,224]. Also, these estrogenic metabolites of DHT were shown to have anticancer properties. A total of 0.1 µM (and concentrations below) 3β-Adiol diminished proliferation and increased the apoptosis of both androgen-sensitive and CRPC cells [225,226,227]. Accordingly, the proliferation of established tumors in PC3 xenograft mice tumor models was substantially reduced by a 3-week treatment with 3β-Adiol [226].

Apigenin-activates ER-Beta

Apigenin The antiproliferative effect of apigenin seems to be mediated through the activation of ERβ

Of note, apigenin treatment significantly decreased the viability of cancer cells and augmented apoptosis, in contrast to the low magnitude of effects observed in non-neoplastic cells [312,332], indicating a selectivity over PCa cells.

Daidzein

Similar to other flavonoids, daidzein has antiproliferative effects in PCa cells (Figure 4). Exposure of PC3 cells to a soy isoflavone concentrate highly enriched in daidzein caused the accumulation of cells in the G2/M phase of the cell cycle, underpinned by the increased expression of p21 [374].
This isoflavone has been shown to interact with ERβ with some selectivity [364,386], and novel daidzein analogs showed anticarcinogenic activity in PCa cells through ERβ mediation [387]

Genistein

Genistein, chemically known as 4′,5,7-trihydroxyisoflavone, is the main isoflavone present in the human diet, as it is predominantly included in the composition of soybeans, peas, lentils, and other beans [433]. This compound has been shown to interact with both ER isoforms, being one of the most potent phytoestrogens stimulating the transcriptional activity of both ERα and ERβ [364]. However, genistein interaction with ERα was shown to be one-thousandth of the potency of E2, whereas for ERβ, the potency was one-third of that of E2 [364]. Therefore, it is the selective binding to ERβ that sustains the genistein anticancer activity [364,434,435]. Nevertheless, genistein action through GPER has been reported in other types of cancer except PCa [436,437].

From a therapeutic perspective, the beneficial effects of genistein, when joined with classical chemotherapy and antiandrogenic drugs, are worth noting. In fact, this isoflavonoid has been tested in clinical trials with PCa patients with promising results. [397,491,492,493,494,495,496,497].
———————
Resveratrol

Resveratrol Reduces ER-alpha, Increases ER-Beta expression.

Resveratrol In fact, the antiproliferative effect of resveratrol has been associated with its ability to reduce ERα and increase ERβ expression [634,635]

25) Harper, Curt E., et al. “Resveratrol suppresses prostate cancer progression in transgenic mice.” Carcinogenesis 28.9 (2007): 1946-1953.

Abstract Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anticancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate males were fed resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at 5 weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate, resveratrol significantly inhibited cell proliferation, increased androgen receptor, estrogen receptor-beta, and insulin-like growth factor-1 receptor, and significantly decreased insulin-like growth factor (IGF)-1 and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate, resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter insulin-like growth factor-1 receptor and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 +/- 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2 and the increase in the putative tumor suppressor, estrogen receptor-beta, provide a biochemical basis for resveratrol suppressing prostate cancer development.

========================================

Prostate Cancer Caused By Catechol Estrogen Quinones

26) Yang, Li, et al. “Novel biomarkers for risk of prostate cancer: results from a case–control study.” The Prostate 69.1 (2009): 41-48.

Although the estrogens estrone and estradiol are recognized to play very important roles in the risk of developing prostate cancer (Pca), the molecular mechanism by which estrogens initiate and/or promote Pca is still unknown. Substantial evidence supports that specific metabolites of estrogens, catechol estrogen quinones, can react with DNA to form depurinating estrogen‐DNA adducts. Apurinic sites derived from depurination of these adducts can induce mutations leading to cancer. Once released from DNA, depurinating estrogen‐DNA adducts are shed from cells into the bloodstream and excreted in urine. By analyzing profiles of estrogen metabolites, conjugates, and depurinating DNA adducts in urine from men with and without prostate cancer, potential biomarkers of Pca can be detected. The goal of this case–control study was to detect and identify potential biomarkers of Pca.
METHODS Urine samples from fourteen cases, men diagnosed with Pca, and 125 controls, men who had not been diagnosed with Pca, were partially purified by solid phase extraction and analyzed by ultraperformance liquid chromatography/tandem mass spectrometry. The urinary levels of androgens, estrogens, estrogen metabolites, conjugates and depurinating DNA adducts were measured.

RESULTS The ratio of depurinating estrogen‐DNA adducts to the sum of the corresponding estrogen metabolites and conjugates was significantly higher in cases (median: 57.34) compared to controls (median: 23.39) (P < 0.001).
CONCLUSIONS This study suggests that depurinating estrogen‐DNA adducts could serve as potential biomarkers to predict risk of Pca. They also could be useful tools for early clinical diagnosis and development of suitable strategies to prevent Pca.

27) Cavalieri, Ercole, and Eleanor Rogan. “The 3, 4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers.” International Journal of Molecular Sciences 22.15 (2021).

===============================================

Silybin silymarin for prostate cancer

28) Ray, Pantha Prodip, et al. “A comprehensive evaluation of the therapeutic potential of silibinin: a ray of hope in cancer treatment.” Frontiers in Pharmacology 15 (2024): 1349745.

Silibinin inhibits the growth of human, mouse, and rat prostate cancer cells, as well as the formation of human prostate tumor xenografts in nude mice. It has also shown suppression of prostate cancer growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. Silibinin has entered phase I/II clinical trials in prostate cancer patients, and preliminary results suggest the need for further investigation in a broader patient population (Singh and Agarwal, 2006).

29) Singh, Rana P., and Rajesh Agarwal. “Prostate cancer prevention by silibinin.” Current cancer drug targets 4.1 (2004): 1-11.
More importantly, silibinin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice.

30) Singh, Rana P., and Rajesh Agarwal. “Prostate cancer chemoprevention by silibinin: bench to bedside.” Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center 45.6 (2006): 436-442.

31) Singh, Rana P., et al. “Silibinin suppresses in vivo growth of human prostate carcinoma PC-3 tumor xenograft.” Carcinogenesis 28.12 (2007): 2567-2574.

32) Singh, Rana P., et al. “Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice.” Clinical Cancer Research 14.23 (2008): 7773-7780.

33) Raina, Komal, et al. “Dietary feeding of silibinin inhibits prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate model.” Cancer research 67.22 (2007): 11083-11091.

34) Deep, G., et al. “Silymarin and silibinin cause G1 and G2–M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silibinin with flavanolignan mixture silymarin.” Oncogene 25.7 (2006): 1053-1069.

35) Ting, Harold, Gagan Deep, and Rajesh Agarwal. “Molecular mechanisms of silibinin-mediated cancer chemoprevention with major emphasis on prostate cancer.” The AAPS journal 15 (2013): 707-716.

36) Wu, Kai-jie, et al. “Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression.” Acta Pharmacologica Sinica 30.8 (2009): 1162-1168.

37) Zi, Xiaolin, and Rajesh Agarwal. “Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention.” Proceedings of the National Academy of Sciences of the United States of America 96.13 (1999): 7490.

Here, we show that silibinin decreases intracellular and secreted levels of PSA in human PCA LNCaP cells under both serum- and androgen-stimulated conditions concomitant with inhibition of cell growth via a G1 arrest in cell cycle progression. The G1 arrest by silibinin does not lead to apoptosis but causes neuroendocrine differentiation of the cells.

38) Tyagi, Alpana, et al. “Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells.” The Prostate 53.3 (2002): 211-217.

39) Davis-Searles, Paula R., et al. “Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells.” Cancer research 65.10 (2005): 4448-4457.

Silymarin for BPH

40) Atawia, Reem T., et al. “Role of the phytoestrogenic, pro-apoptotic and anti-oxidative properties of silymarin in inhibiting experimental benign prostatic hyperplasia in rats.” Toxicology letters 219.2 (2013): 160-169.

Thus, this study examined the protective effect of SIL against testosterone-induced BPH in rats. In an initial dose-response study, SIL in a dose of 50mg/kg was the most effective in preventing the rise in prostate weight, prostate weight/body weight ratio and histopathologic changes induced by testosterone. Testosterone significantly decreased ER-β and increased ER-α and AR expressions as compared to the control group and these effects were significantly ameliorated by SIL. Furthermore, SIL significantly protected against testosterone-provoked decline in mRNA expression of P21(WAF1/Cip1) and Bax/Bcl-xl ratio as well as caspase-3 activity. SIL minimized the number of proliferating cell nuclear antigen (PCNA) positive cells as compared to testosterone-treated group. Moreover, SIL significantly blunted the inducible NF-κB expression and restored the oxidative status to within normal values in the prostatic tissues. Collectively these findings elucidate the effectiveness of SIL in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its phytoestrogenic, pro-apoptotic and anti-oxidative properties.

41) Atawia, Reem T., et al. “Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1α, and NF-κB.” Naunyn-Schmiedeberg’s archives of pharmacology 387 (2014): 1131-1140.

ER Beta
=========================================

I3C/DIM for prostate Cancer

42) Tsao, Chih-Wei, et al. “Regulation of carcinogenesis and mediation through Wnt/β-catenin signaling by 3, 3′-diindolylmethane in an enzalutamide-resistant prostate cancer cell line.” Scientific Reports 11.1 (2021): 1239.

===========================================

Urinary Estrogen Profile in Premenopausal Women taking DIM

43) Newman, Mark, and Jaclyn Smeaton. “Exploring the Impact of 3, 3’-Diindolylmethane on the Urinary Estrogen Profile of Premenopausal Women.” (2024).

=========================

Prostate Cancer Protocol ZZ2

Thymoquinone

44) Al‐Trad, Bahaa, et al. “Inhibitory effect of thymoquinone on testosterone‐induced benign prostatic hyperplasia in Wistar rats.” Phytotherapy Research 31.12 (2017): 1910-1915.

45) Kou, Bo, et al. “Thymoquinone inhibits epithelial-mesenchymal transition in prostate cancer cells by negatively regulating the TGF-β/Smad2/3 signaling pathway.” Oncology reports 38.6 (2017): 3592-3598.

Tocotrienol

46) Vraka, P. S., et al. “Equol and genistein enhance the apoptotic effects of γ-and δ-tocotrienols in androgen receptor-positive prostate cancer cells.” Planta Medica 74.09 (2008): PA256.

47) Yang, Chao, and Qing Jiang. “Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice.” (2017): 2242-2242.

48) Moore, Christine A., et al. “γ-Tocotrienol and metformin are cytotoxic to prostate cancer cell lines and exhibit synergy.” (2018): 3977-3977.

49) Sugahara, Ryosuke, et al. “Annatto tocotrienol induces a cytotoxic effect on human prostate cancer PC3 cells via the simultaneous inhibition of Src and Stat3.” Journal of nutritional science and vitaminology 61.6 (2015): 497-501.

50) Luk, Sze Ue, et al. “Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population.” International journal of cancer 128.9 (2011): 2182-2191.

51) Yap, W. N., et al. “γ-Tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways.” British journal of cancer 99.11 (2008): 1832-1841.

52) Srivastava, Janmejai K., and Sanjay Gupta. “Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells.” Biochemical and biophysical research communications 346.2 (2006): 447-453.

53) Campbell, Sharon E., et al. “γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer.” Free Radical Biology and Medicine 50.10 (2011): 1344-1354.

Tocotrienol and HAIR GROWTH

54) Beoy, Lim Ai, Wong Jia Woei, and Yuen Kah Hay. “Effects of tocotrienol supplementation on hair growth in human volunteers.” Tropical life sciences research 21.2 (2010): 91.

55) Samant, G. V., and P. W. Sylvester. “γ‐Tocotrienol inhibits ErbB3‐dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells.” Cell proliferation 39.6 (2006): 563-574.

Tocotrienol and ER-Beta Signalling

56) Comitato, Raffaella, et al. “A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERβ signal transduction.” American Journal of Physiology-Endocrinology and Metabolism 297.2 (2009): E427-E437.

in vitro binding analyses indicated a high affinity of TTs for ERβ but not for ERα. In addition, in ERβ-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ERβ translocation into the nucleus, which in turn activates estrogen-responsive genes (MIC-1, EGR-1 and cathepsin D), as demonstrated by cell preincubation with the ER inhibitor ICI-182,780.

we analyzed the cellular localization of this receptor isoform following TTRF, α-TOC, and TT treatment in MDA-MB-231 breast cancer cells by indirect immunofluorescence. MDA-MB-231 cell line expresses both ERα and ERβ transcripts (data not shown) (70), but only ERβ is expressed at the level of protein (Fig. 4). As shown in Fig. 5, ERβ localization in control MDA-MB-231 cells was predominantly cytoplasmatic, according to previous reports (25, 75), with nuclei only slightly stained. Treatment with TTRF was associated with nuclear staining, and the administration of purified γ-TT or δ-TT induced a more marked signal than the mixture (Fig. 5). On the other hand, no effects were observed in cells treated with α-TT, in agreement with docking simulation and in vitro ligand binding to the purified protein assays. Finally, no effects were observed in cells treated with α-TOC, in agreement with in silico simulations.

57) Nelson, Adam William. Estrogen receptor beta modulates prostate carcinogenesis. Diss. University of Cambridge, 2017.

58) Chaurasiya, Surendra, et al. “Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.” Plos one 15.5 (2020): e0226057.

59) Mak, Paul, et al. “ERβ impedes prostate cancer EMT by destabilizing HIF-1α and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading.” Cancer cell 17.4 (2010): 319-332.

60) Horvath, Lisa G., et al. “Frequent loss of estrogen receptor-β expression in prostate cancer.” Cancer research 61.14 (2001): 5331-5335.

61) Mak, Paul, et al. “ERβ regulation of NF-κB activation in prostate cancer is mediated by HIF-1.” Oncotarget 6.37 (2015): 40247.

62) Nakamura, Yasuhiro, et al. “Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer.” The Prostate 73.6 (2013): 590-595

==============================================

ER-Beta Agonists Against Prostate Cancer

63) Xiao, Long, et al. “Estrogen receptor β suppresses inflammation and the progression of prostate cancer.” Molecular Medicine Reports 19.5 (2019): 3555-3563.

Previous studies demonstrated that estrogen receptor β (ERβ) signaling alleviates systemic inflammation in animal models, and suggested that ERβ‑selective agonists may deactivate microglia and suppress T cell activity via downregulation of nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB). In the present study, the role of ERβ in lipopolysaccharide (LPS)‑induced inflammation and association with NF‑κB activity were investigated in PC‑3 and DU145 prostate cancer cell lines. Cells were treated with LPS to induce inflammation, and ELISA was performed to determine the expression levels of inflammatory cytokines, including tumor necrosis factor‑α (TNF‑α), monocyte chemoattractant protein 1 (MCP‑1), interleukin (IL)‑1β and IL‑6. MTT and Transwell assays, and Annexin V/propidium iodide staining were conducted to measure cell viability, apoptosis and migration, respectively. Protein expression was determined via western blot analysis. LPS‑induced inflammation resulted in elevated expression levels of TNF‑α, IL‑1β, MCP‑1 and IL‑6 compared with controls. ERβ overexpression significantly inhibited the LPS‑induced production of TNF‑α, IL‑1β, MCP‑1 and IL‑6. In addition, the results indicated that ERβ suppressed viability and migration, and induced apoptosis in prostate cancer cells, which was further demonstrated by altered expression of proliferating cell nuclear antigen, B‑cell lymphoma 2‑associated X protein, caspase‑3, E‑cadherin and matrix metalloproteinase‑2. These effects were reversed by treatment with the ERβ antagonist PHTPP or ERβ‑specific short interfering RNA. ERβ overexpression reduced the expression levels of p65 and phosphorylated NF‑κB inhibitor α (IκBα), but not total IκBα expression in LPS‑treated cells. In conclusion, ERβ suppressed the viability and migration of the PC‑3 and DU145 prostate cancer cell lines and induced apoptosis. Furthermore, it reduced inflammation and suppressed the activation of the NF‑κB pathway, suggesting that ERβ may serve roles as an anti‑inflammatory and anticancer agent in prostate cancer.

ER-Beta Agonists in Ovarian Cancer

two natural ERβ agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer

64) Liu, Jinyou, et al. “Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer.” Oncotarget 8.30 (2017): 50002.
Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Emerging evidence suggests that ovarian cancer cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in ovarian cancer remains elusive. We tested the utility of two natural ERβ agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERβ ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERβ agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERβ agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERβ interacts with p65 subunit of NF-κB and ERβ overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERβ agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.

ER Beta Agonists Breast Cancer

65) Ramasamy, Kumaraguruparan, et al. “Therapeutic use of estrogen receptor β agonists in prevention and treatment of endocrine therapy resistant breast cancers: observations from preclinical models.” Progress in Molecular Biology and Translational Science. Vol. 151. Academic Press, 2017. 177-194.
Breast cancer is one of the most common cancers in the world. The majority of breast cancers express estrogen receptor (ER)α, and endocrine therapy is the primary therapeutic approach to treat ER positive breast cancers. However, developing resistance and side effects are common events of these therapeutic strategies. Recent studies have evaluated the role of ERs sub types and demonstrated that ERα is a tumorigenic and ERβ functions as a tumor suppressor. In recent years, preclinical studies focused on the use of natural and synthetic ERβ agonists to treat wide varieties of cancers, including breast cancer. Successful studies conducted so far, have established that ERβ agonists are effective both alone and in combination with chemotherapeutic agents. These data have suggested that use of ERβ agonists in combination with endocrine therapy may be an effective treatment strategy in hormone receptor positive breast cancers. The present review focuses on the tumor suppressive role of ERβ, and the efficacy and mechanisms of several natural and synthetic ERβ agonists against breast cancer.

ER-Beta Agonist for Lymphoma

ER-Beta expressed in Mantle Cell Lymphoma

66) Yakimchuk, Konstantin, et al. “Inhibition of lymphoma vascularization and dissemination by estrogen receptor β agonists.” Blood, The Journal of the American Society of Hematology 123.13 (2014): 2054-2061.
Key Points Estrogen receptor β (ERβ) activation inhibits lymphoma growth, vascularization, and dissemination in vivo. ERβ activation may mechanistically explain differences in gender incidence and prognosis and contribute to new therapies of lymphomas.
Abstract Most lymphomas show an increased incidence and poorer prognosis in males vs females, suggesting endocrine regulation. We have previously shown that tumor growth in vivo of a murine T-cell–derived lymphoma is repressed following activation of estrogen receptor β (ERβ, ESR2). By using ERβ-deficient mice, we now demonstrate that this inhibition is mediated via a direct effect on the tumor cells and not on the microenvironment. Furthermore, we show that the growth-suppressing effects of ERβ agonist are also valid for human B-cell lymphomas as demonstrated in tumors derived from Granta-519 mantle cell lymphoma (MCL) and Raji Burkitt lymphoma (BL) cells. In Granta-519 MCL tumors, activation of ERβ reduced expression of BAFF and GRB7, 2 important molecules involved in B-cell proliferation and survival. Importantly, activation of ERβ inhibited angiogenesis and lymphangiogenesis, possibly mediated by impaired vascular endothelial growth factor C expression. Furthermore, using disseminating Raji BL cells, we show that ERβ activation reduces dissemination of grafted Raji BL tumors. We also show by immunohistochemistry that ERβ is expressed in primary MCL tissue. These results suggest that targeting ERβ with agonists may be valuable in the treatment of some lymphomas, affecting several aspects of the malignant process, including proliferation, vascularization, and dissemination.

——————————–

THC upregulates ER Beta

67) Takeda, Shuso, et al. “Δ9-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ).” Chemical research in toxicology 26.7 (2013): 1073-1079.

====================================

Pterostilbene for Prostate cancer

68) Dhar, Swati, et al. “Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer.” Oncotarget 7.14 (2016): 18469.
Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.

69) Kumar, Avinash, Agnes M. Rimando, and Anait S. Levenson. Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer. Annals of the New York Academy of Sciences 1403.1 (2017): 15-26.

In our published studies, we identified resveratrol-regulated miRNA profiles in prostate cancer. Resveratrol downregulated the phosphatase and tensin homolog (PTEN)-targeting members of the oncogenic miR-17 family of miRNAs, which are overexpressed in prostate cancer. We have functionally validated the miRNA-mediated ability of resveratrol and its potent analog pterostilbene to rescue the tumor suppressor activity of PTEN in vitro and in vivo. Taken together, our findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.

Pterostilbene

70) Youlin, Kuang, et al. “Inhibition of miR-20a by pterostilbene facilitates prostate cancer cells killed by NK cells via up-regulation of NKG2D ligands and TGF-β1down-regulation.” Heliyon 9.4 (2023).

71) Jawad, Mohammed Ridha, and Ghaith Ali Jasim. “Pterostilbene Effect on Inflammatory and Oxidation Markers in Benign Prostatic Hyperplasia Rats Model.” Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512) 33.2 (2024): 14-19.

72) Chen, Yuhua, et al. “Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation.” Cellular & Molecular Biology Letters 29.1 (2024): 114.

73) Lin, Victor Chia-Hsiang, et al. “Activation of AMPK by pterostilbene suppresses lipogenesis and cell-cycle progression in p53 positive and negative human prostate cancer cells.” Journal of agricultural and food chemistry 60.25 (2012): 6399-6407.

74) Zook, Phillip A. “Chemopreventive Effects of Pterostilbene in Metastatic Prostate Cancer Cells.” (2014).

Pancreatic Cancer

75) Mannal, Patrick W., et al. “Pterostilbene inhibits pancreatic cancer in vitro.” Journal of Gastrointestinal Surgery 14.5 (2010): 873-879.

Breast Cancer

76) Wakimoto, Rei, et al. “Differential anticancer activity of pterostilbene against three subtypes of human breast cancer cells.” Anticancer Research 37.11 (2017): 6153-6159.

Colon Cancer

77) Nutakul, Wasamon, et al. “Inhibitory effects of resveratrol and pterostilbene on human colon cancer cells: a side-by-side comparison.” Journal of agricultural and food chemistry 59.20 (2011): 10964-10970.

78) Wang, Yanshang, et al. “Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells.” American journal of translational research 4.1 (2012): 44.

79) Li, Kun, et al. “Pterostilbene acts through metastasis- associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer.” PloS one 8.3 (2013): e57542.

80) Tsai, Hui-Yun. Growth inhibitory effects of 3’-hydroxypterostilbene in human prostate cancer cells and xenograft mice. Diss. Rutgers University- Graduate School-New Brunswick, 2016.

81) Kumar, Avinash, Agnes M. Rimando, and Anait S. Levenson. “Resveratrol and pterostilbene as a microRNA‐mediated chemopreventive and therapeutic strategy in prostate cancer.” Annals of the New York Academy of Sciences 1403.1 (2017): 15-26.

==============================================

Treating Elevated PSA with Antibiotics by Marc Greenstein , Health Guide

82) Schaeffer, Anthony J., et al. “Treatment of chronic bacterial prostatitis with levofloxacin and ciprofloxacin lowers serum prostate specific antigen.” The Journal of urology 174.1 (2005): 161-164.

PURPOSE: We compared baseline and post-therapy prostate specific antigen (PSA) in patients with chronic bacterial prostatitis who were treated with levofloxacin or ciprofloxacin.

MATERIALS AND METHODS: Subset analysis was done using a randomized, multicenter, double-blind, active control trial of 500 mg levofloxacin daily for 28 days vs 500 mg ciprofloxacin twice daily in 28 days in men with chronic bacterial prostatitis.

RESULTS: Of the 377 men in the intent to treat population, including 197 treated with levofloxacin and 180 treated with ciprofloxacin, 35 on levofloxacin and 37 on ciprofloxacin with baseline PSA greater than 4 ng/ml were included in this analysis. Excluded from analysis were 2 levofloxacin treated patients with extremely high PSA at baseline (62 and 103 ng/ml, respectively).

Mean baseline PSA +/- SD in the patients analyzed was 8.33 +/- 4.46 ng/ml, which decreased to 5.36 +/- 3.82 ng/ml after therapy.

CONCLUSIONS: Approximately 20% of patients diagnosed with chronic bacterial prostatitis had increased PSA. A significant decrease in PSA was observed in these patients after treatment with levofloxacin or ciprofloxacin.

83) Guercio, Stefano, et al. “PSA decrease after levofloxacin therapy in patients with histological prostatitis.” Arch Ital Urol Androl 76.4 (2004): 154-158.
RESULTS: A total of 26 outpatients were evaluated (median age = 65 years). Median total serum PSA concentrations, before and after LVX therapy, were 7.1 ng/ml (range 4.1-15 ng/ml) and 5.8 ng/ml (2-15 ng/ml), respectively (p= n.s). The median reduction of total PSA was 16.6% (range 5.7 – 63.6%).

CONCLUSIONS: Treatment with LVX significantly reduced PSA values in over half of the patients with asymptomatic prostatitis, elevated total PSA and normal DRE and urinalysis. This approach could be applied in the ambulatory setting in order to increase the specificity

84) Bozeman, Caleb B., et al. “Treatment of chronic prostatitis lowers serum prostate specific antigen.” The Journal of urology 167.4 (2002): 1723-1726.

We evaluated men with documented chronic prostatitis and elevated serum prostate specific antigen (PSA) to determine whether treatment with antibiotics and anti-inflammatory drugs lowers serum PSA.

MATERIALS AND METHODS: We retrospectively reviewed the records of 95 men who presented with serum PSA greater than 4 ng./ml. and were subsequently diagnosed with chronic prostatitis with greater than 10 white blood cells per high power field in expressed prostatic excretions. Patients meeting these criteria were treated with a 4-week course of antibiotics and a nonsteroidal anti-inflammatory agent. In all patients followup PSA was determined within 2 months of treatment.

RESULTS: Mean PSA decreased 36.4% from 8.48 ng./ml. before to 5.39 after treatment (p <0.001). In 44 patients (46.3%) serum PSA decreased to below 4 ng./ml. (mean 2.48) and these patients no longer had an indication for biopsy. In the remaining 51 patients serum PSA remained elevated at greater than 4 ng./ml. and they underwent double sextant transrectal ultrasound guided biopsy. Pathological study showed prostate cancer in 13 cases (25.5%), chronic inflammation in 37 (72.5%) and only benign prostatic hypertrophy in 1 (1.05%). PSA in the 13 patients with prostate cancer decreased with treatment only 4.8% from 8.32 to 7.92 ng./ml. (p >0.05). Followup PSA at a mean of 11.4 months was determined in 19 of the 44 men who responded to treatment. Mean PSA increased only 4.5% from 2.35 to 2.46 ng./ml. (p >0.05) during this followup interval.

CONCLUSIONS: In almost half of the patients diagnosed with elevated PSA and chronic prostatitis serum PSA normalized with treatment and there was no longer an indication for transrectal ultrasound guided biopsy. Our study suggests that chronic prostatitis is an important cause of elevated PSA and when it is identified, treatment can decrease the percent of negative biopsies.

85) Magri, Vittorio, et al. “Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection.” ARCHIVIO ITALIANO DI UROLOGIA ANDROLOGIA 79.2 (2007): 84.

We identified from our clinical database a total of 471 patients with PSA > or =4 ng/mL, were subjected to a 6-week course of 500 mg/day ciprofloxacin, 500 mg/day azithromycin (3 days/week), 10 mg/day alfuzosin and 320 mg b.i.d. Serenoa repens extract.

In summary, combination pharmacological therapy decreased the number of patients undergoing prostatic biopsy from 111 to 45. Normalization of PSA values in 59.4% of patients–not subjected to biopsy–increased the prostate cancer detection rate from 12.6% (14/111) to 31.1% (14/45).

=================================

Sulforaphane

86) Kamal, Mohammad M., et al. “Sulforaphane as an anticancer molecule: Mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems.” Archives of pharmacal research 43 (2020): 371-384.

Cancer Stem Cell Agent

87) Coutinho, Leandro de Lima, Tharcísio Citrangulo Tortelli Junior, and Maria Cristina Rangel. “Sulforaphane: An emergent anti-cancer stem cell agent.” Frontiers in Oncology 13 (2023): 1089115.

88) Kaiser, Anna E., et al. “Sulforaphane: A broccoli bioactive phytocompound with cancer preventive potential.” Cancers 13.19 (2021): 4796.

89) Gasmi, Amin, et al. “Anticancer activity of broccoli, its organosulfur and polyphenolic compounds.” Critical Reviews in Food Science and Nutrition 64.22 (2024): 8054-8072.

90) Asif Ali, Muhammad, et al. “Anticancer properties of sulforaphane: current insights at the molecular level.” Frontiers in oncology 13 (2023): 1168321.

broccoli sprouts are the chief source of sulforaphane and are 20 to 50 times richer than mature broccoli as they contain 1,153 mg/100 g. SFN is a secondary metabolite that is produced as a result of the hydrolysis of glucoraphanin (a glucosinolate) by the enzyme myrosinase.

it is a biologically active phytochemical that has many biological properties, such as anti-inflammatory, anticancer, cardioprotective, antioxidative, cytoprotective, DNA protective, and antimicrobial properties. Additionally, it is also a potent immune booster and detoxifier (9, 14)

SFN protects against cancer by inhibiting cancer cell proliferation, arresting the cell cycle, and enhancing the process of apoptosis

Another randomized double-blinded study disclosed that sulforaphane is highly effective in reducing serum prostate-specific antigen (PSA) levels. Serum PSA levels are usually high in men suffering from prostate cancer after radical prostatectomy. The study inferred that the administration of 60 mg SFN in the form of a tablet significantly reduced the PSA progression after at least 3 months of treatment (77).

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

91) Cipolla, Bernard G., et al. “Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy.” Cancer prevention research 8.8 (2015): 712-719.

Treatment comprised daily oral administration of 60 mg of a stabilized free SF for 6 months (M0 to M6) followed by 2 months without treatment (M6 to M8). The study was designed to detect a 0.012 log (ng/ml)/month decrease in the log PSA slope in the SF group from M0 to M6. The primary end-point was not reached. For secondary end-points, median log PSA slopes were consistently lower in SF-treated men. Mean changes in PSA levels between M6 and M0 were significantly lower in the SF group (+0.099 ± 0.341 ng/ml) compared with placebo (+0.620 ± 1.417 ng/ml; p = 0.0433). PSA doubling time was 86% longer in the SF than in the placebo group (28.9 and
15.5 months, respectively). PSA increases >20% at M6 were significantly greater in the placebo group (71.8%) than in the SF group (44.4%); p=0.0163. Compliance and tolerance were very good. SF effects were prominent within 3 months of intervention (M3 to M6). After treatment, PSA slopes from M6 to M8 remained the same in the two arms.

A recent study suggested that sulforaphane is highly beneficial in preventing ulcerative disease by inhibiting the growth of Helicobacter pylori. As per the group of Akinori Yanaka, the consumption of broccoli sprouts consecutively for 2 months can downgrade the colonization of the bacterium. This poses a cancer-preventive effect because of the reduction in oxidative stress caused by H. pylori (78).

===========================================
Phytochemicals AntiProstate CA

92) Mazurakova, Alena, et al. “Anti-prostate cancer protection and therapy in the framework of predictive, preventive and personalised medicine—comprehensive effects of phytochemicals in primary, secondary and tertiary care.” EPMA Journal 13.3 (2022): 461-486.

Broccoli isothiocyanates

Broccoli is a rich source of biologically active isothiocyanates, including sulforaphane and iberin. Importantly, broccoli consumption interacts with glutathione S-transferase mu 1 (GSTM1) genotype modulating signalling pathways associated with inflammation and carcinogenesis in the prostate; the authors also observed changes in TGFβ receptor pathway, insulin signalling, and EGF receptor signalling in men on the broccoli diet. These results provide a mechanistic basis for the effects of broccoli in decreasing PCa risk [66]. Furthermore, a recent study (2020) evaluating chemo-preventive effects of broccoli sprout extract (BSE) demonstrated 40 differentially expressed genes correlating with BSE treatment, including AMACR and ARLNC1, two genes implicated in PCa development. However, the authors observed no effects on other evaluated markers, such as HDAC activity [67].

Milk thistle (silibinin)

Milk thistle (Silybum marianum) is a therapeutic herb with a 2000 history of use. Milk thistle contains a mixture of flavonolignans known as silymarin while silibinin (also known as silybin) represents its main component [68]. A flavonoid silibinin exerts anti-cancer efficacy including potent inhibitory effects on apoptosis, proliferation, angiogenesis or metastasis associated with prostate carcinogenesis [69]. Recent study also demonstrated the effects of silibinin in decreasing aggressive phenotype in an in vitro model of obesity and PCa. Indeed, silibinin mitigated increased cell growth and invasive capacity of PCa cells exposed to sera of the obese and overweight males. These results indicate the beneficial PCa-protective effects of silibinin in obese or overweight males [70]. Therefore, based on the potent results of preclinical anti-cancer evaluations, silibinin advanced into clinical trials [71]. The evidence of initial clinical evaluations of the effects of silibinin in advanced PCa patients demonstrated oral silybin-phytosome, a commercially available formulation that contains silibinin, in a dose of 13 g/daily delivered in three divided doses to be safe and well tolerated [72]. Moreover, a phase II study revealed that the same dose oral silybin-phytosome achieved high blood concentrations transiently but low levels in prostate tissue of patients with localised PCa [73].

An absolute majority of altogether 30 clinically relevant studies dedicated to phytochemicals in the PCa primary prevention which we have identified in the literature, demonstrated positive effects and potentially reduced risks of the disease development such as listed by references [33, 34, 45, 49]. To this end, we do strongly recommend the stratification of affected individuals in sub-optimal health conditions by phenotyping for targeted PCa-prevention and identification of the most effective plant-based treatment options [3, 49, 105, 107].

The effects of plant-derived phytochemicals were evaluated for secondary care particularly focused on reducing risks of the disease progression. By evaluating randomly selected clinical trials (29 studies in total), almost 70% were identified as demonstrating positive effects of phytosubstances in reducing risks of PCa progression such as listed by references [35, 76]. Moreover, several studies included in our review highlighted supportive and stimulating effects of conventional anti-cancer therapy as well as an evident mitigation of their adverse effects [21–26].

===================================================

Minocycline for Prostate Cancer

Search Terms: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C10&q=minocycline+prostate+cancer&btnG=

——————————————————————– –

Minocycline for Prostate Cancer

93) Regen, Francesca, et al. “Striking growth-inhibitory effects of minocycline on human prostate cancer cell lines.” Urology 83.2 (2014): 509-e1.

Abstract Objective: To elucidate a hypothetical link between retinoic acid (RA) signaling and minocycline for targeting prostate carcinoma (PCA). RA signaling has been implicated in growth-inhibition of malignant PCA, and intracellular RA homeostasis has been investigated as a potential therapeutic target. Minocycline is a tetracycline antibiotic with pleiotropic actions in many tissues and reaches comparably high levels in human prostate tissue. Interestingly, minocycline exhibits the rare side effect of a pseudotumor cerebri, which is otherwise known to occur from vitamin A intoxication or in retinoid therapy. Therefore, we hypothesized minocycline to putatively interact with intracellular RA homeostasis in PCA.

Methods: Using LN-CAP, DU-145, and PC-3 cell lines, effects of minocycline on microsomal RA metabolism and on cell growth were assessed in vitro.

Results: Minocycline was identified to potently inhibit cell growth, at concentrations within the range of tissue levels readily reached under standard therapeutic conditions. In vitro inhibition experiments revealed inhibition of RA breakdown, yet only at comparably high concentrations of minocycline. Using all trans-RA, RA metabolism inhibitor liarozole, and different retinoid receptor antagonists, the putative RA-dependent effects of minocycline were further evaluated and confirmed to be independent of RA signaling.

Conclusion: Our findings add to the growing body of evidence for the many pleiotropic actions of minocycline. In view of the striking effects of minocycline on cell growth in PCA cell lines in vitro and its relatively safe side effect profile, the use of minocycline for targeting PCA should be timely clinically evaluated.

94) Turanli, Beste, et al. “Drug repositioning for effective prostate cancer treatment.” Frontiers in physiology 9 (2018): 500.

Minocycline Has anti-cancer activities against various cancer cell lines, such as ovarian cancer, glioma, PCa, melanoma, and breast cancers

Minocycline has been in phase 2 of clinical trials for different carcinomas such as myeloma, esophageal, pancreatic, colorectal,lung, head, and neck cancers (Bhattarai et al., 2016) whereas in phase 3 of clinical trials for PCa.

Minocycline is a semi-synthetic tetracycline derivative that maintains the efficacy against both Gram-positive and Gram-negative bacteria. It has been approved by FDA, more than 30 years ago, for the treatment of acne and some sexually transmitted diseases. Subsequently, experimental models revealed non-antibiotic properties of minocycline and determined minocycline beneficial against various disorders with an inflammatory basis such as dermatitis, periodontitis,
atherosclerosis, and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (Garrido-Mesa et al., 2013). Minocycline inhibits the action of proinflammatory cytokines and matrix metalloproteinases (MMPs) which are extracellular matrix-degrading enzymes implicated in cancer invasion and metastasis. Up until now, the drug presents anti-cancer activities against various cancer cell lines, such as ovarian cancer, glioma, PCa, melanoma, and breast cancers (Lokeshwar, 2011; Ataie-Kachoie et al., 2013; Garrido-Mesa et al., 2013). Moreover, minocycline has been in phase 2 of clinical trials for different carcinomas such as myeloma, esophageal, pancreatic, colorectal,lung, head, and neck cancers (Bhattarai et al., 2016) whereas in phase 3 of clinical trials for PCa. Lokeshwar (2011) investigated doxycycline, minocycline, and chemically modified tetracycline (CMT) analogs for treatment of PCa. Some of these CMTs, notably, CMT-3 and CMT-308, were found significantly more potent than doxycycline or minocycline in inhibiting tumor cell-derived MMPs and inducing apoptosis in vitro and in vivo. In another study, pharmacokinetic interactions for minocycline with retinoic acid metabolism were
investigated in various PCa cell lines (Regen et al., 2014).

Minocycline

minocycline (100 mg twice daily)

95) Garrido‐Mesa, N., A. Zarzuelo, and Jz Gálvez. “Minocycline: far beyond an antibiotic.” British journal of pharmacology 169.2 (2013): 337-352.

———————————–

Minocycline for Ovarian Cancer

96) Pourgholami, Mohammad H., et al. “Minocycline inhibits growth of epithelial ovarian cancer.” Gynecologic oncology 125.2 (2012): 433-440.

97) Pourgholami, Mohammad Hossein, et al. “Minocycline inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways.” Gynecologic oncology 129.1 (2013): 113-119.

99) Ataie-Kachoie, Parvin, et al. “Minocycline attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies.” American journal of cancer research 5.2 (2015): 575.

100) Ataie-Kachoie, et al. “Minocycline suppresses interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: in vitro and in vivo studies.” PloS one 8.4 (2013): e60817.

101) Ataie Kachoie, Parvin. Evaluation of minocycline for the treatment of epithelial ovarian cancer: a preclinical study. Diss. UNSW Sydney, 2013.

102) Ataie-Kachoie, Parvin, Samina Badar, and David L. Morris. “Minocycline targets NF-B pathway through suppression of TGF-1-TAK1-I B kinase axis in ovarian cancer: in vitro and in vivo studies.”

Colo-Rectal Cancer

103) Yang, Ling, et al. “Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer.” International Journal of Biological Sciences 18.6 (2022): 2540.
————————
Glioblastoma

neuroprotective effects in experimental models of stroke, trauma, and neurodegenerative disorders like multiple sclerosis, Huntington disease, and Parkinson

immunomodulatory, neuroprotective, antiapoptotic, and antiinflammatory effects [8–11] and inhibitory effects on proteolysis, angiogenesis, and metastasis of the tumor [12–14], independent of its antimicrobial activity.

104) Afshari, Amir R., Hamid Mollazadeh, and Amirhossein Sahebkar. “Minocycline in treating glioblastoma multiforme: far beyond a conventional antibiotic.” Journal of oncology 2020.1 (2020): 8659802.
The second-generation semisynthetic tetracycline analog used for over 30 years is minocycline (7-dimethylamino-6-desoxytertracycline) [3].

This highly lipophilic molecule can easily cross the blood-brain barrier (BBB) and has demonstrated neuroprotective effects in experimental models of stroke, trauma, and neurodegenerative disorders like multiple sclerosis, Huntington disease, and Parkinson [4].

Mechanistically, minocycline seems to have potential biological activities including immunomodulatory, neuroprotective, antiapoptotic, and antiinflammatory effects [8–11] and inhibitory effects on proteolysis, angiogenesis, and metastasis of the tumor [12–14], independent of its antimicrobial activity. In many of these reports, the mechanisms for anti-inflammatory, immunomodulating, and neuroprotective effects of minocycline have been discussed, such as inhibitory impacts on the activities of inducible nitric oxide (NO) synthase (iNOS) and matrix metalloproteinases (MMPs), cyclooxygenase (COX)/lipoxygenase (LOX) inhibition, suppression of caspase-1/-3/-8 activation, inhibition of p38 mitogen-activated protein kinase (MAPK) phosphorylation, the blockage of poly (ADP-ribose) polymerase 1 (PARP-1) activation, downregulation of proapoptotic proteins (Bax, Bak, and Bid), an upregulation in antiapoptotic protein Bcl-2, consequently protecting the cells from apoptosis [15–17]. Nonetheless, these antiapoptotic effects come from disorders involving excessive apoptosis [18]. Cellular apoptosis is, however, strongly downregulated in cancer [19].

Interestingly, minocycline is extremely useful in reducing MMPs expression released by bone tumor cells [30]. In this regard, Niu et al. have suggested that combined use of celecoxib (a COX-2 inhibitor) and minocycline has promising inhibitory effects on the metastasis of breast cancer, as compared to celecoxib or minocycline alone [31].

Suppress IL-6

For instance, minocycline could suppress IL-6 as well as inhibiting invasion, migration, and adhesion capacity of ovarian cancer cells in vitro and in vivo [33]

Prevents NF-KB activation

minocycline prevents NF-κB activation and nuclear translocation, which inhibits the target-gene expression of MMP-9 in breast and ovarian cancer cells, resulting in reduced cell fusion frequency [33, 35].

It has been shown that minocycline could suppress endothelial cell neovasculogenic activity by reducing VEGF secretion from cancer cells [48]. Besides, a combination of minocycline and irinotecan reduces VEGF and IL-8 cytokine induction, thus enhancing the anticancer effects of minocycline alone or in combination with an alkylating agent [49].

105) Liu, Wei-Ting, et al. “Minocycline inhibits the growth of glioma by inducing autophagy.” Autophagy 7.2 (2011): 166-175.

Neuroprotection- Minocycline Inhibits microglia activation in hippocampus

106) Dai, Jiajia, et al. “Minocycline relieves depressive-like behaviors in rats with bone cancer pain by inhibiting microglia activation in hippocampus.” Anesthesia & Analgesia 129.6 (2019): 1733-1741.

Non-Small Cell Lung Cancer

107) Tone, Mari, et al. “Impact of minocycline on outcomes of EGFR-mutant non-small cell lung cancer patients treated with EGFR-Tkis.” Scientific Reports 13.1 (2023): 8313.

108) Thottian, A. G. F., et al. “Evaluation of safety and efficacy of minocycline combined with tyrosine kinase inhibitors in patients of EGFR mutated metastatic lung cancer.” Annals of Oncology 30 (2019): ii76.

Breast Cancer

109) Rezaei, Abedeh, et al. “Minocycline induced apoptosis and suppressed expression of matrix metalloproteinases 2 and 9 in the breast cancer MCF-7 cells.” Molecular Biology Reports 51.1 (2024): 463.

120) Bernemann, Christof, and Ludwig Kiesel. “Improvement of response to chemotherapy in breast cancer cells by the use of the non-oncologic drug minocycline.” Cancer Research 75.15_Supplement (2015): 3496-3496.

Inhibition of Angiogenesis

121) Jung, Hui-Jung, et al. “Minocycline inhibits angiogenesis in vitro through the translational suppression of HIF-1α.” Archives of biochemistry and biophysics 545 (2014): 74-82.

122) Tamargo, Rafael J., Robert A. Bok, and Henry Brem. “Angiogenesis inhibition by minocycline.” Cancer research 51.2 (1991): 672-675.

Pancreatic Cancer

123) Quinn, Bridget A., et al. “Pancreatic cancer combination therapy using a BH3 mimetic and a synthetic tetracycline.” Cancer research 75.11 (2015): 2305-2315.

Leukemia

124) Song, Hairong, et al. “Cytotoxic effects of tetracycline analogues (doxycycline, minocycline and COL-3) in acute myeloid leukemia HL-60 cells.” PloS one 9.12 (2014): e114457.

125) Fares, Mona, et al. “DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline-and minocycline-induced cell death in the K562 leukemic cell line.” Biochemical and biophysical research communications 463.3 (2015): 268-274.

Renal Cancer

126) Masumori, Naoya, et al. “Inhibitory effect of minocycline on in vitro invasion and experimental metastasis of mouse renal adenocarcinoma.” The Journal of urology 151.5 (1994): 1400-1404.

127) Masumori, N., et al. “Minocycline inhibits in vitro invasion and experimental pulmonary metastasis of mouse renal adenocarcinoma.” Advances in dental research 12.1 (1998): 111-113.

Hepatoocellualar CA

128) Liu, Fu-Yao, et al. “Minocycline and cisplatin exert synergistic growth suppression on hepatocellular carcinoma by inducing S phase arrest and apoptosis.” Oncology reports 32.2 (2014): 835-844.

————————
Review 2024
pharmacological mechanisms of preventive and therapeutic effects of minocycline.
ovarian cancer, breast, glioma, colorectal, liver, pancreatic, lung, prostate, melanoma, head and neck, leukemia, and non-cancer diseases such as Alzheimer’s disease, Parkinson, schizophrenia, multiple sclerosis, Huntington, polycystic ovary syndrome, and coronavirus disease 19. Minocycline may be a potential medication for these disorders due to its strong blood–brain barrier penetrance.

129) Rezaei, Abedeh, Amin Moqadami, and Mohammad Khalaj-Kondori. “Minocycline as a prospective therapeutic agent for cancer and non-cancer diseases: a scoping review.” Naunyn-Schmiedeberg’s Archives of Pharmacology 397.5 (2024): 2835-2848.

Minocycline is an FDA-approved secondary-generation tetracycline antibiotic. It is a synthetic antibiotic having many biological effects, such as antioxidant, anti-inflammatory, anti-cancer, and neuroprotective functions. This study discusses the pharmacological mechanisms of preventive and therapeutic effects of minocycline. Specifically, it provides a comprehensive overview of the molecular pathways by which minocycline acts on the different cancers, including ovarian, breast, glioma, colorectal, liver, pancreatic, lung, prostate, melanoma, head and neck, leukemia, and non-cancer diseases such as Alzheimer’s disease, Parkinson, schizophrenia, multiple sclerosis, Huntington, polycystic ovary syndrome, and coronavirus disease 19. Minocycline may be a potential medication for these disorders due to its strong blood–brain barrier penetrance. It is also widely accepted as a specific medication, has a well-known side-effect characteristic, is reasonably priced, making it appropriate for continuous use in managing diseases, and has been demonstrated as an oral approach because it is effectively absorbed and accomplished almost all of the body’s parts.

—————————-
Minocyline Treatment of Sarcoidosis

130) Miyazaki, Eishi, et al. “Minocycline for the treatment of sarcoidosis: is the mechanism of action immunomodulating or antimicrobial effect?.” Clinical rheumatology 27 (2008): 1195-1197.

131) Bachelez, Hervé, et al. “The use of tetracyclines for the treatment of sarcoidosis.” Archives of dermatology 137.1 (2001): 69-73.

132) Sasaki, Shinichi, et al. “Management of skin sarcoidosis with minocycline monotherapy.” Respirology Case Reports 7.4 (2019): e00413.

133) Park, DJ John, et al. “Minocycline for the treatment of ocular and ocular adnexal sarcoidosis.” Archives of ophthalmology 125.5 (2007): 705-709.

====================================
Minocycline as Anti-Viral

Influenza

134) Saha, Priyanka, et al. “Unveiling the Antiviral Potential of Minocycline: Modulation of Nuclear Export of Viral Ribonuclear Proteins during Influenza Virus Infection.” Viruses 16.8 (2024): 1317.

Covid

135) Singh, Harmanjit, Ashish Kumar Kakkar, and Prerna Chauhan. “Repurposing minocycline for COVID-19 management: mechanisms, opportunities, and challenges.” Expert Review of Anti-Infective Therapy 18.10 (2020): 997-1003.

RSV

136) Bawage, Swapnil S., et al. “Antibiotic minocycline prevents respiratory syncytial virus infection.” Viruses 11.8 (2019): 739.

West Nile virus (WNV) [15], Japanese encephalitis virus (JEV) [16], and DENV

137) Cao, Mengtao, et al. “Minocycline Inhibits Tick-Borne Encephalitis Virus and Protects Infected Cells via Multiple Pathways.” Viruses 16.7 (2024): 1055.
While minocycline’s antiviral properties have been extensively studied and it has been proven to be effective against various viruses in the Orthoflavivirus genus, such as West Nile virus (WNV) [15], Japanese encephalitis virus (JEV) [16], and DENV [17], its specific therapeutic impact on TBEV infection has not yet been reported.

West Nile Virus

138) Michaelis, Martin, et al. “Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells.” Journal of Antimicrobial Chemotherapy 60.5 (2007): 981-986.

Dengue Fever virus

139) Leela, Shilpa Lekshmi, et al. “Drug repurposing of minocycline against dengue virus infection.” Biochemical and biophysical research communications 478.1 (2016): 410-416.

140) Lai, Yen-Chung, et al. “Minocycline suppresses dengue virus replication by down-regulation of macrophage migration inhibitory factor-induced autophagy.” Antiviral Research 155 (2018): 28-38.

———————————– — —

141) Trusov, N. V., et al. “Effects of combined treatment with resveratrol and indole-3-carbinol.” Bulletin of experimental biology and medicine 149 (2010): 213-218.

142) Mohammadi, Saeed, et al. “Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line.” Journal of receptors and signal transduction 37.5 (2017): 506-514.

143) Tutelyan, V. A., et al. “Indole-3-carbinol induction of CYP1A1, CYP1A2, and CYP3A1 activity and gene expression in rat liver under conditions of different fat content in the diet.” Bulletin of experimental biology and medicine 154 (2012): 250-254.

144) Ociepa-Zawal, Marta, et al. “The effect of indole-3-carbinol on the expression of CYP1A1, CYP1B1 and AhR genes and proliferation of MCF-7 cells.” Acta Biochimica Polonica 54.1 (2007): 113-117.

145) Weng, Jing-Ru, et al. “Indole-3-carbinol as a chemopreventive and anti-cancer agent.” Cancer letters 262.2 (2008): 153-163.

146) Wang, Thomas TY, et al. “Estrogen receptor α as a target for indole-3-carbinol.” The Journal of nutritional biochemistry 17.10 (2006): 659-664.

147) Sundar, Shyam N., et al. “Indole-3-carbinol selectively uncouples expression and activity of estrogen receptor subtypes in human breast cancer cells.” Molecular Endocrinology 20.12 (2006): 3070-3082.

148) Peng, Chunting, et al. “Indole-3-carbinol ameliorates necroptosis and inflammation of intestinal epithelial cells in mice with ulcerative colitis by activating aryl hydrocarbon receptor.” Experimental Cell Research 404.2 (2021): 112638.

149) Busbee, Philip B., et al. “Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner.” JCI insight 5.1 (2020).

—————————-

Anti-Inflammatory Effects of 2MEO

150) Bourghardt, Johan, et al. “The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice.” Endocrinology 148.9 (2007): 4128-4132.
En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo.

151) Dantas, Ana Paula V., and Kathryn Sandberg. “Does 2-methoxyestradiol represent the new and improved hormone replacement therapy for atherosclerosis?.” Circulation research 99.3 (2006): 234-237.

152) Chakrabarti, Subhadeep, Olga Lekontseva, and Sandra T. Davidge. “Estrogen is a modulator of vascular inflammation.” IUBMB life 60.6 (2008): 376-382.

153) Stubelius, Alexandra, et al. “Role of 2-methoxyestradiol as inhibitor of arthritis and osteoporosis in a model of postmenopausal rheumatoid arthritis.” Clinical Immunology 140.1 (2011): 37-46.

153) Shand, Francis Henry Warner, et al. “In vitro and in vivo evidence for anti-inflammatory properties of 2-methoxyestradiol.” Journal of Pharmacology and Experimental Therapeutics 336.3 (2011): 962-972.

154) Sutherland, Tara E., et al. “2-Methoxyestradiol–a unique blend of activities generating a new class of anti-tumour/anti-inflammatory agents.” Drug discovery today 12.13-14 (2007): 577-584.

155) Huerta-Yepez, S., et al. “2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model.” Clinical immunology 129.2 (2008): 313-324.

156) Hu, Qiang, et al. “2-Methoxyestradiol alleviates neuroinflammation and brain edema in early brain injury after subarachnoid hemorrhage in rats.” Frontiers in Cellular Neuroscience 16 (2022): 869546.

157) Chen, Ying-Yin, et al. “Anticancer Drug 2‐Methoxyestradiol Protects against Renal Ischemia/Reperfusion Injury by Reducing Inflammatory Cytokines Expression.” BioMed research international 2014.1 (2014): 431524.

158) Yan, Chunguang, et al. “2-Methoxyestradiol protects against IgG immune complex-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein β activities.” Molecular Immunology 85 (2017): 89-99.

159) Plum, Stacy M., et al. “Disease modifying and antiangiogenic activity of 2-methoxyestradiol in a murine model of rheumatoid arthritis.” BMC musculoskeletal disorders 10 (2009): 1-13.

160) Schaufelberger, Sara A., et al. “2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism.” American Journal of Physiology-Endocrinology and Metabolism 310.5 (2016): E313-E322.

161) Singh, Purnima, et al. “Central CYP1B1 (Cytochrome P450 1B1)-estradiol metabolite 2-methoxyestradiol protects from hypertension and neuroinflammation in female mice.” Hypertension 75.4 (2020): 1054-1062.

162) Song, Chi Young, et al. “2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A2α Activity in Female Mice.” Hypertension 78.5 (2021): 1368-1381.

163) Zhang, Yong, et al. “Estrogen Metabolite 2-Methoxyestradiol Attenuates Blood Pressure in Hypertensive Rats by Downregulating Angiotensin Type 1 Receptor.” Frontiers in Physiology 13 (2022): 876777.\

164) Azhar, Ahmad S., Ashraf B. Abdel-Naim, and Osama M. Ashour. “2-Methoxyestradiol inhibits carotid artery intimal hyperplasia induced by balloon injury via inhibiting JAK/STAT axis in rats.” Environmental Science and Pollution Research 29.39 (2022): 59524-59533.

165) Kumar, Addanki P., et al. “2-Methoxyestradiol interferes with NFκB transcriptional activity in primitive neuroectodermal brain tumors: implications for management.” Carcinogenesis 24.2 (2003): 209-216.

166) Takata, Hidehiko, et al. “2-methoxyestradiol enhances p53 protein transduction therapy-associated inhibition of the proliferation of oral cancer cells through the suppression of NFkappaB activity.” Acta Medica Okayama 58.4 (2004): 181-187.

167) Yan, Chunguang, et al. “2-Methoxyestradiol protects against IgG immune complex-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein β activities.” Molecular Immunology 85 (2017): 89-99.

168) Yeh, Ching-Hua, et al. “Anticancer agent 2-methoxyestradiol improves survival in septic mice by reducing the production of cytokines and nitric oxide.” Shock 36.5 (2011): 510-516.

169) Duncan, Gordon S., et al. “2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation.” Proceedings of the National Academy of Sciences 109.51 (2012): 21034-21039.

170) Mal, Rahul, et al. “Estrogen receptor beta (ERβ): a ligand activated tumor suppressor.” Frontiers in oncology 10 (2020): 587386.

171) Hickey, Theresa E., et al. “The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer.” Nature medicine 27.2 (2021): 310-320.

172) Liu, Yanfang, Hong Ma, and Jing Yao. “ERα, a key target for cancer therapy: A review.” OncoTargets and therapy (2020): 2183-2191.

173) Chen, Peng, Bo Li, and Ling Ou-Yang. “Role of estrogen receptors in health and disease.” Frontiers in endocrinology 13 (2022): 839005.

174) Clusan, Léa, et al. “A basic review on estrogen receptor signaling pathways in breast cancer.” International journal of molecular sciences 24.7 (2023): 6834.

175) Abraham, Guy E., Jorge D. Flechas, and J. C. Hakala. “Optimum levels of iodine for greatest mental and physical health.” The Original Internist 9.3 (2002): 5-20.

176) Abraham, Guy E., Jorge D. Flechas, and J. C. Hakala. “Orthoiodosupplementation: Iodine sufficiency of the whole human body.” The Original Internist 9.4 (2002): 30-41.

177) Abraham, Guy E. “The concept of orthoiodosupplementation and its clinical implications.” The Original Internist 11.2 (2004): 29-38.

178) Abraham, Guy E. “The safe and effective implementation of orthoiodosupplementation in medical practice.” The Original Internist 11.1 (2004): 17-36.

179) Abraham, Guy E. “The history of iodine in medicine part I: from discovery to essentiality.” The Original Internist 13.1 (2006): 29-36.

180) Abraham, Guy E. “The historical background of the iodine project.” The Original Internist 12.2 (2005): 57-66.

ER-Beta (Estriol-ER-Beta) (Premarin Bring Steroids ER-Beta) (Prometrium downregulates ER Alpha) (Androgens – 3BetaDiol)

181) Mancuso, M., et al. “Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer.” Carcinogenesis 30.2 (2009): 340-347.

These and previous data from studies in rodents (30) suggest that estrogens may be key modulators of skin tumorigenesis. The effects of estrogens are mediated by estrogen receptor (ER)-a and ERb, members of the nuclear steroid receptor superfamily. Both ERs have been detected in the skin of rodents and humans, though with distinct expression patterns (36); specifically, ERb has been indicated as the predominant ER in human scalp skin (37), whereas in murine skin both ERs are expressed during hair follicle cycling in hair cycle-dependent manner (38).

In ovariectomized Ptch1þ/ and Car-S females, basal and squamous tumor induction were drastically increased over intact controls (CNs), and restored to levels observed in males, showing that endogenous estrogens play a critical role in protection against BCC and SCC carcinogenesis by diverse agents in mouse skin.

The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. However, the local level of each sexual steroid depends on the expression of androgen-and estrogen-synthesizing enzymes in different cell types (50). The role of estrogen in the regulation of hair follicle cycling in mice was rediscovered in the past decade, following a seminal paper by Oh et al. (33), showing that an ER pathway within the dermal papilla regulates the telogen–anagen follicle transition and that 17-b-estradiol blocks hair growth and arrests hair follicles in telogen.

Experimental data from the present study support the concept that
female sex hormones can be protective in non-melanoma skin carcinogenesis; in fact, we found that skin tumor development was significantly enhanced after ovarian hormone withdrawal in two independent experimental models. The results shown here demonstrate increased skin tumor incidence and multiplicity and decreased tumor latency in ovariectomized versus CN females, regardless of the nature of the keratinocyte-initiating agent (i.e. chemical for SCC and physical for BCC). Remarkably, malignant progression of benign papillomas to SCC occurred almost exclusively in OVX Car-S and was rare in CN females following two-stage carcinogenesis by DMBA/TPA.

To shed light on potential mechanisms involved in estrogen modulation of skin tumor progression, we examined ER protein levels in benign skin papillomas from the different Car-S groups. Immunoblots of papilloma extracts showed significantly increased expression of ERa and downregulation of ERb in tumors from OVX relative to
CN tumors, suggesting a role of the ratio ERa:ERb in susceptibility of skin to estrogen-modulated carcinogenesis, and a correlation of decreased ERb expression with increased malignant progression of initially benign papillomas in ovariectomized Car-S mice.

Previous studies have established a complex relationship between ERs and cyclin D1, with important implications for proliferation of estrogen-responsive tissues and deregulation of proliferation in cancer (42,43). To further explore this issue, we analyzed tumors for expression of cyclin D1, which among D-type cyclins controlling cell cycle regulation has been most directly implicated in oncogenesis. In the presence of estrogen, cyclin D1 is one important target gene through which estrogen-complexed ERa mediates its proliferative action, whereas estrogen-complexed ERb represses cyclin D1 gene transcription and blocks ERa-mediated induction when both receptors are present (56).

In the absence of estrogen, however, cyclin D1 is able to bind to and activate transcription mediated by ER-alpha (42,43,57). Significantly, we detected cyclin D1 upregulation in tumors from OVX relative to CN mice. Thus, our results suggest that in tumors from intact mice, where the ratio ERa:ERb is low, the protective role of ER-beta may be privileged over the proliferation stimulus mediated by the a-isoform, whereas in tumors from ovariectomized animals, the inverted ERa:ERb ratio may favor proliferation and malignant progression, possibly due to the oncogenic role of cyclin D1. This hypothesis is supported by the higher proliferation rate observed in papillomas from OVX compared with intact CN mice, a finding also observed in ER-positive breast cancer, where high cyclin D1 expression correlates with high Ki67 expression (58). We cannot exclude, however, that ovariectomy may modulate other factors involved in the regulation of skin development and functions, such as progesterone levels (59) and that this modulation may in turn influence tumor development.

In summary, our study shows for the first time a protective role of endogenous estrogen against basal and squamous skin tumorigenesis caused by physical or chemical agents in independent mouse models Finally, our study suggests that reciprocal expression of ERa and ERb may be associated with estrogen-mediated modulation of squamous epithelial carcinogenesis, with a key role played by cyclin D1.

================================

===================RESUME HERE========================

Index Cracking Cancer

p 214 Pterostilbene and Prostate cancer

In 2013, Drs. Steven Dias and Dr. Kun Li et al. delved into the molecular biology of pterostilbene’s anti-cancer activity using prostate cancer in a mouse xenograft model and came out with two important papers. The authors showed pterostilbene had higher potency for inhibiting tumor progression than resveratrol. (9–10) Dr. Diaz concluded:

3M-Res [pterostilbene] was the most active in inhibiting [cancer] cell proliferation
and suppressing colony formation, and its accumulation in both serum and
tumor tissues was the highest … findings offer strong preclinical evidence for the
utilization of dietary stilbenes, particularly 3M-Res [pterostilbene], as novel, potent,
effective chemopreventive agents in prostate cancer. (9)

Pterostilbene, the Most Promising

In 2013, Dr. Kun Li reported that pterostilbene appears to be the most promising of the resveratrol analogs and significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis in a mouse model of prostate cancer by inhibiting MTA1 (metastasis associated protein 1). (10)

Dias, Steven J., et al. “Trimethoxy‐Resveratrol and Piceatannol Administered Orally Suppress and Inhibit Tumor Formation and Growth in Prostate Cancer Xenografts.” The Prostate 73.11 (2013): 1135-1146.

Li, Kun, et al. “Pterostilbene acts through metastasis- associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer.” PloS one 8.3 (2013): e57542.

p 222 Prostate cancer prevention/therapy (52–54)

Tsai, Hui-Yun. Growth inhibitory effects of 3’-hydroxypterostilbene in human prostate cancer cells and xenograft mice. Diss. Rutgers University- Graduate School-New Brunswick, 2016.

Dhar, Swati, et al. “Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer.” Oncotarget 7.14 (2016): 18469.

======================================

IV Vitamin C for Prostate Cancer

Garcia, Keishla M., et al. “Intravenous Vitamin C and Metabolic Correction as Adjuvant Therapy for prostate Cancer: a Case Report.” (2016).Intravenous Vitamin C for prostate Cancer Case Report Garcia Keishla 2016

==========================================

Doxycyxline in vitro prostate Cancer

Fife, Rose S., et al. “Effects of doxycycline on human prostate cancer cells in vitro.” Cancer letters 127.1 (1998): 37-41.
Prostate cancer is the most common form of cancer in older men and the major cause of death from prostate cancer is metastatic disease. The matrix metalloproteinases (MMPs) play a significant role in the growth, invasion and metastasis of many tumors, including those of the prostate. We previously demonstrated that doxycycline, a synthetic tetracycline, inhibits MMPs and cell proliferation and induces apoptosis in several cancer cell lines. We also demonstrated that in an in vivo model of metastatic breast cancer in athymic mice doxycycline inhibits tumor size and regrowth after resection. In the present study, gelatinolytic activity in the human prostate cancer cell line, LNCaP, was suppressed and significant inhibition of cell growth occurred after exposure to 5 or 10 microg/ml of doxycycline, while cell growth was normal in untreated cells. Radioisotope incorporation into proteins was reduced by doxycycline. DNA fragmentation, consistent with apoptosis, was demonstrated in cells treated with doxycycline. These data suggest that doxycycline may have potential utility in the management of prostate cancer.

Lokeshwar, Bal L., et al. “Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model.” International journal of cancer 98.2 (2002): 297-309.
Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI50] = 5.0 µg/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G0/G1 compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27–35%) and lung metastases were observed (28.9 ± 15.4 sites/animal [CMT-3-treated] versus 43.6 ± 18.8 sites/animal [DC-treated] versus 59.5 ± 13.9 [control]; p < 0.01]. A delay in tumor growth (27 ± 9.3%, p < 0.05), reduction in metastases (58 ± 8%) and decrease in tumor incidences (55 ± 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.

 

https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=c56d0794ad44ec327a8969f7d7f65d2b8a17d088

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Marshall Protocol !
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Marshall, Trevor G., and Frances E. Marshall. “Sarcoidosis succumbs to antibiotics—implications for autoimmune disease.” Autoimmunity reviews 3.4 (2004): 295-300.

Occult bacteria in sarcoid tissue

For several decades there have been consistent reports of occult bacteria being found in tissue taken from sarcoidosis patients. Cantwell [6], Mattman [7], Wirostko [8] and Moskovic [9] have all documented the appearance of a special type of tiny microbe, coccoid forms known as cell wall deficient (CWD) bacteria. Cantwell recently summarized the historical perspective in an excellent review ‘Bacteria in sarcoidosis and a rationale for antibiotic therapy in this disease’ [10], which contains numerous color micrographs of these bacterial forms. Cantwell also reported similar bacteria in tissue from SLE patients [11

3. Cell wall deficient bacteria

CWD bacteria are resistant to most antibiotics,
being pleomorphic forms of active spirochetal and
blood-borne species. They proliferate very slowly,
and are very difficult to culture. They have adap-
ted to a hostile environment by shedding their cell
walls. The pleomorphism from blood-borne to th

Some of these CWD bacterial species have adapted
to live within the phagocytes of the immune system. The very cells, which are supposed to kill the invading bacteria, actually provide them refuge. These CWD bacteria are so tiny that 10 (or more) can live in the cytoplasm of the same phagocyte. Wirostko et al. [8], photographed CWD bacteria living within several cells of the immune system:
monocytes, lymphocytes and polymorphonuclear leucocytes. A stunning micrograph from Nilsson et al. [14], shows a (presumed) Rickettsia bacterium replicating within the cytoplasm of a phagocyte from a sarcoid-osis patient. Here was evidence that not only could bacteria adapt to live in this harsh environment, but that they could also flourish.

As the bacteria are killed there is a massive release of the same cytokines as are gradually released during normal disease activity. Unless the antibiotic dosage is carefully controlled, adverse events may include both life-threatening pulmonary insufficiency and life-threatening cardiac events. Even though JHS presents a major problem with patient management and antibiotic dosing, its pres

4. Jarisch-Herxheimer shock

Even though JHS presents a major problem with patient management and antibiotic dosing, its presence is also proof-positive of a bacterial disease process, and that bacteria are being killed by the antibiotic therapy.

In many ways sarcoidosis is the ideal test-bed to develop antibiotic therapies against these occult bacteria. The JHS symptoms allow therapy to be optimized in ways that would not be possible in inflammatory disease exhibiting a lesser degree of JHS.

5. Minocycline and doxycycline in sarcoidosis

Bachelez et al. [18], described how minocycline effectively treated skin lesions in 10 patients from a cohort of 12. Two patients also exhibited pulmonary manifestations of the disease, and these were also put into remission by a 12-month course of minocycline

In that context the results achieved by this team were stunning and revolutionary. However, their achievements were marginalized within the sarcoidosis clinical community,which characterized the minocycline treatment as maybe being useful for skin lesions, but overlooked the improvement in pulmonary manifestations

Take-home messages

. Sarcoid inflammation has now succumbed to antibiotics in two independent trials, demonstrating, ex juvantibus, a primary, homogenous, bacterial pathogenesis.

. Low-dose minocycline is the antibiotic capable of inducing remission in sarcoidosis. A dual
regimen of low-dose azithromycin + minocycline is especially effective.

. Jarisch-Herxheimer shock is a major problem. Unless the antibiotic dosage is carefully controlled, adverse events may include both life threatening pulmonary insufficiency and life-
threatening cardiac events.

. The pathogens appear to be multiple species of tiny, slow growing, cell-wall-deficient
(CWD) bacteria living within the cytoplasm of phagocytes.

. The secosteroid hormone 1,25-dihydroxyvitamin- D is elevated in patients with Th1 immune inflammation, while the precursor, 25-hydroxy-vitamin-D, is depressed.

. 1,25-dihydroxyvitamin-D metabolism is similarly disturbed in (at least) rheumatoid arthritis, SLE, and Parkinson’s, and it is likely that these diseases also have a bacterial Th1 pathogenesis

2012 Moscow Marshall

Click to access Marshall_Moscow_2012_Immunophysiology.pdf

Marshall, Trevor G. “Microbial Metagenomics–Predicting and Preventing human chronic disease.”

25-hydroxyvitamin-D
1,25-dihydroxyvitamin-D,

VDR dysfunction is an Predictive marker for chronic inflammatory disease

We have previously reported8, based on data from patients with a variety of chronic diagnoses, that the active metabolite 1,25-dihydroxyvitamin-D, which is rarely measured, is elevated in a majority of patients with chronic inflammatory disease. Further, the precursor, 25-hydroxyvitamin-D, is most often expressed well below the 50 nanomolar level at which it starts to exert its immunosuppressive activity.
Measurement of these two metabolites can give early prediction that an individual is accumulating a microbiota which is likely to lead to immune dysfunction, and chronic inflammatory disease.

Olmesartan

A decade ago, we identified that the drug Olmesartan, developed to treat hypertension and having as its primary target the Angiotensin II Receptor, was capable of being retargeted to reactivate the VDR.

We set up an International network of clinical collaborators, and started collecting a stream of observational data from individuals with diagnoses ranging from Sarcoidosis to CFS/ME, from Multiple Sclerosis to Bipolar Affective Disorder, from Rheumatoid Arthritis to Amyotrophic Lateral Sclerosis

Both SSRI and NSAIDS heavily suppress the immune system, inhibiting the immunostimulative
activity of the Olmesartan, and terminating recovery.

The disease model is also needed, for example, to understand the surge in creatinine some patients experience as they recover. We have seen creatinine surge to five times normal without any harm accruing to the individual.

We saw Sarcoidosis Xrays and CT scans become clear, we saw patients rejoining family life, patients going back to work.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076734/
Proal, Amy D., et al. “Immunostimulation in the era of the metagenome.” Cellular & molecular immunology 8.3 (2011): 213-225.

Over the past 8 years we have developed a therapy for autoimmune disease that appears to strongly activate the innate immune response. Treatment is based on the use of a putative VDR agonist, olmesartan medoxomil, which, by re-activating the receptor, appears to gradually restore expression of the numerous AmPs, Toll-like receptors (TLRs) and other antimicrobials expressed by the VDR.

Olmesartan medoxomil was developed as a mild hypotensive, an angiotensin II type 1 receptor antagonist. Typically it is dosed 20–40 mg once a day. However, this drug has a unique affinity for the VDR nuclear receptor, for which it is most probably a partial agonist.38, 77 In order to be effective in this targeting, the dosing has to be more frequent as the VDR’s half-life is only 4–6 h before it is broken apart by caspase-3, and protease activity.78 Thus, when dosed at 4- to 8-h intervals, VDR stimulation persists between doses.

Olmesartan has at least two identified effects on the immune system. By inhibiting angiotensin II binding to its receptor, which occurs under most dosing regimes, the expression of nuclear factor-kappaB is reduced.79 This lowers the cell’s production of inflammatory cytokines. We have found that as the dosing interval shortens, immune activation becomes noticeable above about 20 mg every 8 h, achieving saturation at about 40 mg every 6 h. Patients have reported a further palliative effect at even higher doses, but the exact mechanism for this has not yet been validated.

However, there are definite sequelae that some might consider to be ‘adverse events’—autoimmune patients initiating this therapy appear to experience immunopathology, sometimes severe immunopathology. They generally report consistent increases in overall malaise, particularly those related to the specific symptoms of their disease. At the same time, markers of inflammation rise. It should be noted that healthy people administered with the same medications experience no such reaction.80

After months, or sometimes years of dealing with these symptomatic flares, the very symptoms that wax and wane in accordance with administration of olmesartan begin to disappear, resulting in reports of symptomatic improvement and, in some cases, eventual resolution of the symptoms. Inflammatory markers generally return to their normal range.

For example, LZ is a 58-year-old female diagnosed with rheumatoid arthritis in 1996. In the 5 years that followed, she was administered with high-dose antibiotics along with frequent cortisone injections. Despite treatment, her disease progressed and she had joint damage in hands and feet. In 2001, LZ began 2000–5000 IU of vitamin D daily, dehydroepiandrosterone, armor thyroid, hydrocortisone and bioidentical hormone supplementation. In August 2004, LZ’s measured levels of ANA were 1∶160. Following the test, patient stopped vitamin D and was administered with 40 mg of olmesartan four times daily. Over the course of several years, she was prescribed rotating combinations of certain subinhibitory antibiotics including minocycline, azithromycin and clindamycin. This caused transient increases in symptoms of depression, gastrointestinal distress and joint pain. In March 2005, ANA antibodies were measured at 1∶320 while in August of the same year, this measure declined to 1∶160. By August 2006, LZ was able to discontinue both Celebrex and all hormone therapy. One year later, LZ reported being able to hike with reduced joint pain. In November 2006 and in eight subsequent tests, the patient tested negative for ANA antibodies (Figure 1). In December 2007, LZ discontinued all antibiotics but continues to take olmesartan.

The following case history illustrates how, when certain subinhibitory antibiotics are taken in conjunction with the immunostimulant olmesartan, patients generally become much more sensitive to these antibiotics.

BG is a 56-year-old male who was first diagnosed with rheumatoid arthritis in June 2002. He also complained of fatigue and depression. In February 2004, BG was administered with 200 mg of minocycline every other day, 200 mg of Celebrex daily and Advil as needed. BG reported improvement in all major symptoms within weeks. In April 2005, Celebrex was lowered to 100 mg every day. At this point, BG reported being ‘unaware’ of rheumatoid arthritis symptoms. On a scale of 1–10, with 10 being the most severe, he rated his overall well-being as a 1. In September 2005, he was administered with 40 mg of olmesartan four times daily. His symptom levels remained constant. After 2 weeks, 25 mg of minocycline every other day was introduced. Within 48 h, BG reported exquisite photosensitivity, complaining that daylight ‘hurt his eyes’ and ‘made him feel ill’. Over the course of several weeks, his symptoms increased greatly to the point where he rated his overall well-being as an 8.5. After 5 weeks, BG discontinued olmesartan and resumed 200 mg of minocycline every other day. He reported immediate relief. In September 2005, BG resumed olmesartan four times daily and 25 mg of minocycline on alternate days. He experienced a spike in symptoms once more. Over a few months, immunopathology gradually decreased on this dose. At present, BG has been on the treatment for over 4 years. In September 2010, BG reported overall well-being at a 2.
\\

Many patients experience an inflammatory reaction for several years before reporting significant improvement. While we expected immunopathology as a result of olmesartan administration to occur for at least several months, we did not anticipate how profound and prolonged the reaction could be. In our experience, patients with severe illness often manage immunopathology for 4–7 years before presenting with objective markers indicating significant improvement or disease resolution.

As we have discussed, our immunopathology-inducing protocol can cause a sustained exacerbation in symptoms over at least several years. However, in spite of the treatment’s length, we have found many patients are more than willing, considering the gravity of the prognoses they face, to commit themselves to such therapy.

Waterhouse, Joyce C., Thomas H. Perez, and Paul J. Albert. “Reversing bacteria‐induced vitamin D receptor dysfunction is key to autoimmune disease.” Annals of the New York Academy of Sciences 1173.1 (2009): 757-765.

pdf
Marshall, Trevor G., Belinda J. Fenter, and Frances E. Marshall. “Antibacterial Therapy Induces Remission in Sarcoidosis.” Journal of Independent Medical Research.[[101]↩] (2005).

Antibiotic and Dosing Guidelines

It is clear that the bacteria causing sarcoid inflammation do not succumb to the antibiotics
that are in common usage. If this were the case, then the bacterial pathogenesis of
sarcoidosis would have become obvious long ago, based on unexpected ‘spontaneous
remission’ concurrent with antibiotic therapies for other conditions.
Partly this is because many of the species do not succumb to any one antibiotic (they are
‘antibiotic-resistant’) and partly it is because the dosing regimes in common usage do not
work well when treating the bacteria populating the immune system of sarcoid patients.
Minocycline is the only antibiotic monotherapy that can usually be relied upon to start
reducing a sarcoid patient’s bacterial load. But Minocycline’s action against the intra-
cellular bacteria is not achieved with normal dosing regimens. As noted by Brown [20],
Minocycline is most effective when its concentration in the bloodstream is allowed to
decay between successive doses. With a pharmacokinetic half-life around 17 hours, the
dosing schedule proposed by Brown (of Monday, Wednesday and Friday) meets that
criteria. We have also used a 48 hour interval in our own dosing guidelines, depending on
the preferences of the individual patient. The starting dose of Minocycline should be no
greater than 25mg every 48 hours. Even this low dosage has caused significant breathing
difficulties for some of the most severely ill patients. We suggest increasing the dose
based on the patient’s ability to tolerate the JHS, and we try to maintain the patients on
Minocycline (alone) for the first three months of therapy. It is important to note that
Doxycycline is not effective on as wide a spectrum of bacteria as Minocycline. In
particular, Doxycycline seems ineffective against the aerobic bacteria that populate the
lungs. It is our opinion that Doxycycline should not be used in any therapy for
Sarcoidosis.
When the patient can tolerate the JHS resulting from 100mg of Minocycline every 48
hours, we add one quarter of a 250mg Azithromycin tablet (=62mg), once a week. We
find it generally takes several months before the average patient is able to gradually
increase the Azithromycin dosage to a full 250mg weekly, while maintaining 100mg of
minocycline every 48 hours. At this point a little Sulfamethoxazole/Trimethoprim can be
added to the 48 hour Minocycline to potentiate activity against additional resistant
species [39]

http://www.ra-infection-connection.com/MarshallProtocol.htm
Marshall Protocol Summary: Inflammation in RA, Fibromyalgia, and Sarcoidosis
INDEX

Prof Trevor Marshall on vitamin D and Olmesartan, May 27, 2010
Prof Trevor Marshall co-Chairs and keynotes the session on Vitamin D at the Ljubljana Intl. Congress on Autoimmunity, on May 6, 2010.

————————————————–

Cardiac Sarcoidosis

Kawano, Hiroaki, et al. “Cardiac Sarcoidosis which Occurred four Years after Successful Treatment of Cutaneous Sarcoidosis with Minocycline.” Internal Medicine (2024): 3174-23.

============================================================

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663

my blog: www.jeffreydachmd.com 
Natural Thyroid Toolkit by Jeffrey Dach MD
Cracking Cancer Toolkit by Jeffrey Dach MD
Heart Book by Jeffrey Dach MD
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com
www.drdach.com

Click Here for: Dr Dach’s Online Store for Pure Encapsulations Supplements
Click Here for: Dr Dach’s Online Store for Nature’s Sunshine Supplements

Web Site and Discussion Board Links:

jdach1.typepad.com/blog/
disc.yourwebapps.com/Indices/244066.html
disc.yourwebapps.com/Indices/244067.html
http://sci.med.narkive.com/covV2Qo2/jeffrey-dach-book-announcment-natural-medicine-101

Disclaimer

The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

Link to this Article

Copyright © 2024 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given. See Repost Guidelines.

FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation

Last updated on October 31st, 2024 by Jeffrey Dach MD