Index for Prostate Cancer

Prostate Cancer Index

Cracking Cancer Toolkit Index

p. 23 Proposed List of Drugs for Prostate Cancer

In 2018, Dr. Beste Turanli et al. summarized a proposed list of repurposed drugs for prostate
cancer treatment (27). This list includes:

• Dexamethasone—steroidal, anti-inflammatory
• Aspirin (ASA)—COX-1 and COX-2 inhibitor
• Diclofenac NSAID—COX-2 inhibitor
• Celecoxib NSAID—COX-2 inhibitor
• Minocycline, doxycycline, tetracycline— Antibiotic, anti-inflammatory
• Niclosamide—antiparasitic, potent Wnt/β-catenin inhibitor
• Itraconazole—antifungal; reversed drug resistance by inhibiting
P-glycoprotein, Hedgehog, and Wnt/β- catenin pathways; inhibits angiogenesis
• Digoxin—cardiology drug used for congestive heart failure
• Valproic acid—HDAC inhibitor used for seizure disorder
• Statins—HMG-CoA reductase inhibitors; inhibit mevalonate pathway;
• Mifepristone—progesterone-receptor blocking drug (PR), used as an abortion
drug
• Disulfiram—treatment of alcohol addiction
• Metformin—popular anti-diabetic drug.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962745/
27) Turanli, Beste, et al. “Drug repositioning for effective prostate cancer treatment.” Frontiers in Physiology 9 (2018).

p 50 DCA Induces Protective Autophagy in Colorectal and Prostate CA Model

In 2014, Dr. G. Lin et al. studied DCA in a colorectal and prostate cancer xenograft model
in vivo, expecting to find cancer cells dying from apoptosis. They did not find the expected
apoptosis of cancer cells. Instead, they found increased expression of autophagy after DCA
treatment, both in vitro and in vivo.

The induction of “protective autophagy” by cancer cells is a well-known response to stress
or anti-cancer drug treatment. This can be overcome by adding an autophagy inhibitor drug,
such as propranolol. (DCA synergy with the autophagy inhibitor propranolol is discussed
below.) In addition, Dr. Lin’s group found that DCA treatment increased reactive oxygen species (ROS), inhibited mTOR pathway signaling, and reduced lactate production. (28)

28) Lin, G., et al. “Dichloroacetate induces autophagy in colorectal cancer cells and tumours.” British journal of cancer 111.2 (2014): 375-385.

p 62 Long-Term DCA—Prostate and Epididymis Toxicity

Long term DCA studies in mice show testicular, prostate and epididymis toxicity which
may result in decreased testosterone levels and impaired fertility with reduction in sperm
production. Monitoring testosterone levels is advised when using DCA in males. One study
suggests ingesting palm date fruit extract to prevent DCA induced testicular toxicity. (143-147)

143) Sen, R., et al. “Long-Term Administration of DCA Induces Epididymus Toxixity in Male Albino Rats.” Advances in Pharmacology and Toxicology 17.1 (2016): 21.

144) Sen, R., et al. “A Toxicological Study of Dichloroacetate Acid (DCA) on the Prostate Gland of Male Albino Rats.” Advances in Pharmacology & Toxicology 16.3 (2015).

145) El Arem, Amira, et al. “Dichloroacetic acid-induced testicular toxicity in male rats and the protective effect of date fruit extract.” BMC Pharmacology and Toxicology 18.1 (2017): 17.

p 69 DCA sensitizes prostate CA to Radiation Therapy

134) Cao, Wengang, et al. “Dichloroacetate (DCA) sensitizes both wild‐type and over expressing Bcl‐2 prostate cancer cells in vitro to radiation.” The Prostate 68.11 (2008): 1223-1231.

p 75 Propranolol for Prostate CA

Propranolol has been suggested as an adjunct to breast cancer treatment. Additional studies describe beta blockers conferring similar reduction in cancer mortality in prostate cancer, melanoma, colon, ovarian, prostate, non-small-cell lung, and hepatocellular, multiple myeloma. (37)

37) Barron, Thomas I., et al. “Beta blockers and breast cancer mortality: a population-based study.” J Clin Oncol 29.19 (2011): 2635-2644.

p 78 Propranolol Autophagy Inhibitor!!! Prostate Cancer in Vivo

Combine Propranolol (OXPHOS and Autophagy Inhibitor) w DCA (Glycolysis Inhibitor)

Similar to the Lucido study above, combining propranolol with a glycolysis inhibitor, 2DG
(2-deoxyglucose), was found quite effective in a prostate cancer model in 2018 by Dr. Laura
Brohée et al. who observed that this combination led to a massive accumulation of autophagosomes indicating inhibition of autophagy in the prostate cancer cells. Dr. Brohée’s group write:

The propranolol + 2DG treatment efficiently prevents prostate cancer cell proliferation,
induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial
bioenergetics and aggravates ER [endoplasmic reticulum] stress in vitro and also
suppresses tumor growth in vivo…. . The blockage by propranolol of the autophagy
flux induced by 2-DG resulted in a strong accumulation of LC3-II and p62 and in
a massive accumulation of autophagic vesicles…. Propranolol is also an inhibitor
of the PAP [phosphatidate phosphatase] activity of lipins, which probably explains
why it inhibits autophagy flux. (50)

50) Brohée, Laura, et al. “Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.” Scientific reports 8.1 (2018): 7050.

Note: PAP is a major regulator of lipid metabolism and controls the autophagy process. Both
PAP and Lipin-1 have emerged as good targets for anti-cancer treatment. (51–57)

One might speculate that DCA could serve the same purpose as glycolysis Inhibitor,
replacing the 2-DG in the above study.

p 79 Population Study Beta Blockers Reduce Cancer in HALF

In 2015, Dr. Pig Ying Chang et al. reviewed a database of 24,238 patients over a 12-year
follow-up. Dr. Chang’s group report:

Patients with propranolol treatment exhibited significantly lower risks of cancers in
head and neck (HR: 0.58), esophagus (HR: 0.35), stomach (HR: 0.54), colon (HR: 0.68),
and prostate cancers (HR: 0.52). [HR= Hazard Ratio]. (33)

Propranolol for Prostate cancer (92)(12)(50)

12) Magnon, Claire, et al. “Autonomic nerve development contributes to prostate cancer progression.” Science 341.6142 (2013).

50) Brohée, Laura, et al. “Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.” Scientific reports 8.1 (2018): 7050.

92) Lu, Saihua, et al. “Propranolol Inhibits Androgen Deprivation-induced Neuroendocrine Differentiation of Prostate Cancer.” Pharmacology 15.8 (2019): 986-993

p 97 Melatonin for Prostate Cancer

123) Paroni, Rita, et al. “Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling.” Journal of pineal research 57.1 (2014): 43-52.

p112 Apatone for prostate CA
Apatone is a proprietary solution that combines vitamin K3 and vitamin C.

25) Tareen, Basir, et al. “A 12 week, open label, phase I/IIa study using apatone for the treatment of prostate cancer patients who have failed standard therapy.” Int J Med Sci 5.2 (2008): 62-67.

27) Gilloteaux, Jacques, et al. “Synergistic antitumor cytotoxic actions of ascorbate and menadione on human prostate (DU145) cancer cells in vitro: nucleus and other injuries preceding cell death by autoschizis.” Ultrastructural pathology 38.2 (2014): 116-140.

p 113 Ascorbate for Prostate CA

63) Pollard, Harvey B., et al. “Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer.” in vivo 24.3 (2010): 249-255.

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

Vitamin K2 for Prostate CA p 115

95) Dasari, Subramanyam, et al. “Vitamin K2, a menaquinone present in dairy products targets castration- resistant prostate cancer cell-line by activating apoptosis signaling.” Food and chemical toxicology 115 (2018): 218-227.

96) Dasari, Subramanyam, et al. “Vitamin K and its analogs: Potential avenues for prostate cancer management.” Oncotarget 8.34 (2017): 57782.

p 124 Doxycycline for Prostate Cancer Stem Cells p 124

Prostate cancer stem cells (69–71)

69) Matsumoto, Takashi, et al. “Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity.” Oncogenesis 6.11 (2017): 1-11.

Doxycycline Synergy with DOXO chemotherapy in Prostate CA

70) Zhu, Chao, et al. “Doxycycline synergizes with doxorubicin to inhibit the proliferation of castration-resistant prostate cancer cells.” Acta biochimica et biophysica Sinica 49.11 (2017): 999-1007.

71) Ogut, Deniz, et al. “Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells.” Folia histochemica et cytobiologica 54.4 (2016): 171-180.

p 137 Sulforaphane for prostate Cancer

Sulforaphane Depletes Glutathione (GSH) by 90 Per Cent!!

In 2008, Dr. Clarke found that sulforaphane inhibited prostate cancer cells by downregulating
intracellular glutathione (GSH) and increasing reactive oxygen species (ROS), causing
mitochondrial apoptosis. (78)

In 2005, Dr. Singh reported that sulforaphane caused rapid and marked depletion of
intracellular glutathione levels in prostate cancer cells. He writes:

Sulforaphane [SFN] treatment caused a rapid decline in the level of GSH
[Glutathione]. For instance, the GSH levels in PC-3 [Prostate Cancer] cells treated for
3 and 6 h with 40 μm SFN were reduced by about 90 and 94%, respectively, compared
with controls. (79)

78) Clarke, John D., Roderick H. Dashwood, and Emily Ho. “Multi-targeted prevention of cancer by sulforaphane.” Cancer Letters 269.2 (2008): 291-304.

79) Singh, Shivendra V., et al. “Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species.” Journal of Biological Chemistry 280.20 (2005): 19911-19924.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

p 137 Sulforaphane Randomized Trial in Prostate Cancer

In 2015, Dr. Cipolla did a double-blinded, randomized, placebo-controlled trial of sulforaphane in 78 males with rising PSA levels after radical prostatectomy for prostate cancer. Treatment consisted of 60 mg of sulforaphane for 6 months over which time the sulforaphane group had a mean increase in PSA of 0.01 ng/ml compared to a 0.62 ng/ml increase for placebo. PSA doubling time in the sulforaphane group was 28.9 months compared to 15.5 months for the placebo group. Sulforaphane prolonged PSA doubling time, thus delaying “biochemical recurrence.” (80)

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

———————-

p 137 Pro-Oxidant Sulforaphane Depletes Intracellular Glutathione

In 2017, Dr. DaCosta studied sulforaphane chemoprevention, finding an acute pro-oxidant
effect resulting from depletion of intracellular glutathione. He writes:

Sulforaphane [SFN] actually has an acute pro-oxidant effect in cells, largely by depleting intracellular glutathione due to the formation and export of SFN glutathione complexes [28]. SFN can also increase mitochondrial ROS generation by inhibiting complex III of the mitochondrial respiratory chain, which causes the accumulation of Ubisemiquinone, from which molecular oxygen receives electrons, resulting in the formation of superoxide and hydrogen peroxide. (81)

81) Dacosta, Christopher, and Yongping Bao. “The role of MicroRNAs in the chemopreventive activity of sulforaphane from cruciferous vegetables.” Nutrients 9.8
(2017): 902.

OXPHOS INHIBITOR

p 138 Sulforaphane Inhibits Mitochondrial OXPHOS

Prostate Cancer Studied In Vivo

In 2009, Dr. Xiao studied a sulforaphane in vitro prostate cancer model, finding:
Sulforaphane statistically significant [sic] inhibited activities of mitochondrial respiratory
chain enzymes in LNCaP and PC-3 cells [prostate cancer cell lines]. (85)

p 138 Sulforaphane Induces Protective Autophagy—Prostate CA

In 2006, Dr. Herman-Antosiewicz studied sulforaphane in a prostate cancer cell line,
finding induction of “protective autophagy,” and suggested that the addition of autophagy
inhibitor would be synergistic, writing:

Induction of autophagy represents a defense mechanism against sulforaphane-
induced apoptosis in human prostate cancer cells…. . It is reasonable to
speculate that the cancer chemopreventive activity of sulforaphane may be enhanced
by the simultaneous treatment with an inhibitor of autophagy. (86)

p 138 Autophagy Inhibitor Chloroquine Augments Sulforaphane Prostate CA animal Model

In 2013, Dr. Vyas studied sulforaphane in prostate cancer in mouse xenograft model.
Previous in vitro studies showed sulforaphane causes induction of “protective autophagy” in
prostate cancer cells, which “inhibits apoptotic cell death by delaying release of cytochrome
c due to sequestration of mitochondria in autophagosomes.”

In other words, the mitochondria cannot release apoptotic proteins freely into the cytoplasm
because the mitochondria are sequestered in little bags called autophagosomes.
Addition of autophagy inhibitor, chloroquine, significantly augmented the anti-cancer effects of sulforaphane in this animal model. (87)

Naujokat, Cord, and Dwight L. McKee. “The “Big Five” phytochemicals targeting cancer stem cells: curcumin, EGCG, sulforaphane, resveratrol, and genistein.” Current medicinal chemistry (2021).

p 141 Feverfew (Parthenolide) Prostate cancer stem cells (123)

123) Kawasaki, Brian T., et al. “Effects of the sesquiterpene lactone parthenolide on prostate tumor‐initiating cells: An integrated molecular profiling approach.” The Prostate 69.8 (2009): 827-837.

Curcumin for Prostate CA

9) Mbese, Zintle, Vuyolwethu Khwaza, and Blessing Atim Aderibigbe. “Curcumin and Its Derivatives as Potential Therapeutic Agents in Prostate, Colon and Breast Cancers.” Molecules 24.23 (2019): 4386.

p146 Sulforaphane Mitochondrial ROS in Prostate Cancer

85) Xiao, Dong, et al. “Cellular responses to cancer chemopreventive agent D, L-sulforaphane in human prostate cancer cells are initiated by mitochondrial
reactive oxygen species.” Pharmaceutical Research 26.7 (2009): 1729-1738.

Sulforaphane induces Autophagy

Inhibition of Autophagy Augments Sulforaphane

86) Herman-Antosiewicz, Anna, Daniel E. Johnson, and Shivendra V. Singh. “Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells.” Cancer Research 66.11 (2006): 5828-5835.

88) Kanematsu, Sayaka, et al. “Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells.” Anticancer Research 30.9 (2010): 3381-3390.

89) Nishikawa, Takeshi, et al. “Inhibition of autophagy potentiates sulforaphane-induced apoptosis in human colon cancer cells.” Annals of Surgical Oncology 17.2
(2010): 592-602.

90) Nishikawa, Takeshi, et al. “The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis.” Angiogenesis 13.3 (2010): 227-238

91) Wilcox, Alexander, et al. “Sulforaphane Alters the Acidification of the Vacuole to Trigger Cell Death.” bioRxiv (2018): 371534.

p 149 Quercetin and ECGC Synergy for prostate cancer stem cells

143) Tang, Su-Ni, et al. “The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition.” Journal of Molecular Signaling 5.1 (2010): 14.

p 152 Sulfasalazine and Prostate cancer (16) Cysteine Starvation

16) Doxsee, Daniel W., et al. “Sulfasalazine-induced cystine starvation: Potential use for prostate cancer therapy.” The Prostate 67.2 (2007): 162-171

p 154 Mefloquine in Prostate CA Cell Line

In 2013, Dr. Kun-Huang Yan et al. studied mefloquine in a prostate cancer cell line in vitro
and in vivo finding high cytotoxicity causing cancer cell death, and improved survival of the
treated mice. (41)

41) Yan, Kun-Huang, et al. “Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo.” Oncology letters 5.5 (2013): 1567-1571.

p 171 Pyrvinium is a POTENT Androgen Receptor Blocker

In 2009, Dr. Jeremy Jones et al. found that pyrvinium is a potent androgen receptor
blocker, causing prostate atrophy in mice, and suggested pyrvinium would be useful in treatment of androgen receptor mediated disorders such as “female alopecia, female hirsutism, BPH (benign prostatic hyperplasia), and prostate cancer”. (32)

32) Jones, Jeremy O., et al. “Non-competitive androgen receptor inhibition in vitro and in vivo.” Proceedings of the National Academy of Sciences 106.17 (2009): 7233-7238.

p 176 Aspirin Use and Prostate Cancer Reduces Prostate Cancer RISK 57%

In 2016, Dr. F. Lapi et al. performed a retrospective study of 13,453 patients, finding that
low-dose aspirin use of less than 100 mg per day for five years reduced prostate cancer risk
by 57 per cent. (8)

8) Lapi, F., et al. “Risk of prostate cancer in low dose aspirin users: A retrospective cohort study.” International journal of cancer 139.1 (2016): 205-211.

p 191 Metformin as an Anti-Cancer Stem Cell Agent Inflammatory Prostate Cancer

In 2013, Dr. Heather Hirsch et al. studied a breast cancer mouse xenograft model, finding
metformin “selectively kills” cancer stem cells by inhibiting NF-kB activation and STAT3 activation. Metformin is also effective as a stem cell agent in mouse xenograft studies involving inflammatory prostate cancer and melanoma cell lines. (9)

9) Hirsch, Heather A., Dimitrios Iliopoulos, and Kevin Struhl. “Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth.” Proceedings of the National Academy of Sciences 110.3 (2013): 972-977.

p 192 Synthetic Lethality Metformin (OXPHOS Inhibitor) Combined with/ GLYCOLYSIS Inhibitor 2 DG in Prostate Cancer

Similarly, synthetic lethality was found with combined use of metformin and the glycolysis
inhibitor 2-deoxyglucose (2-DG) in 2016 by Dr. Jie Zhu et al. studying an ovarian cancer cell
model, and in 2010 by Dr. Issam Ben Sahra et al. studying a prostate cancer cell model. (44–45)

One might speculate that other glycolysis inhibitors such as DCA, diclofenac or quercetin
might serve in place of 2-DG. Indeed, synergy of glycolysis inhibitor DCA with OXPHOS inhibitor metformin has been found, as discussed in Chapter 5 on DCA Dichloroactetate.

p 194 96% Inhibition Metformin combined with 2DG for Prostate Cancer

The combination of metformin with the glycolysis inhibitor 2DG was very effective in a
prostate cancer cell model studied by Dr. Issam Ben Sahra et al. in 2010 with 96% inhibition of cell viability in prostate cancer cells. (45) One might expect similar synergy of metformin
with other glycolysis inhibitors such as DCA, quercetin, and diclofenac. (18)(51)

45) Sahra, Issam Ben, et al. “Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.” Cancer research 70.6 (2010): 2465-2475.

p 194 Metformin combined with Chemo Prevents Relapse

In 2013, Dr. Heather Hirsch et al. found metformin effective for inflammatory prostate
cancer cell in vitro and in vivo xenografts. The combination of metformin with doxorubicin
chemotherapy prevented relapse in a mouse xenograft model of prostate cancer, and also in
a lung cancer model. (9)

p 194 METFORMIN Retrospective Metformin Study Shows Significant Clinical Benefit in Prostate Cancer After Radiation Therapy

In 2013, Dr. Daniel Spratt et al. did a retrospective study of 2,901 men followed over 9
years after radiation therapy for prostate cancer showing that those patients taking metformin had “significant clinical benefit.”

After 9 years of follow-up, mortality from prostate cancer was only 2.7% for metformin
users compared to those not using metformin: 22% mortality for diabetics and 8.2% mortality
for non-diabetics not using metformin. I thought this was rather impressive. Dr. Spratt
et al. write:

Metformin decreased the risk of PSA recurrence, distant metastasis, and PCSM [prostate
cancer specific mortality] compared with diabetic non-metformin patients. To our knowledge, this is the first clinical evidence that metformin may improve cancer-specific survival outcomes in prostate cancer. Furthermore, metformin strongly decreased the clinically defined transformation from androgen-sensitive prostate cancer to CRPC [castrate-resistant prostate cancer].

Note: PSA = Prostate Specific Antigen, a common marker for prostate cancer. (52)

52) Spratt, Daniel E., et al. “Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.” European
Urology 63.4 (2013): 709-716.

Metformin and Statin Synergy in Prostate Cancer w bone mets

71) Babcook, Melissa A., et al. “Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer.” Molecular cancer therapeutics 13.10 (2014): 2288-2302.

Curcumin for Prostate CA

28) Sha, Jian, et al. “Curcumin induces G0/G1 arrest and apoptosis in hormone independent prostate cancer DU-145 cells by down regulating Notch signaling.” Biomedicine & Pharmacotherapy 84 (2016): 177-184.

36) Leão, Ricardo, et al. “Cancer stem cells in prostate cancer: Implications for targeted therapy.” Urologia internationalis 99.2 (2017): 125-136.

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
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)

9) 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.

10) 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)

52) 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.

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

54) 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.

p 229 Boswellia Effective for Prostate cancer (46–50)

46) Liu, Yong-qing, et al. “Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties.” Acta Pharmacologica Sinica 40.5 (2019): 689-698.

47) Syrovets T, Gschwend JE, Buchele B, Laumonnier Y, Zugmaier W, Genze F, Simmet T. Inhibition of IκB Kinase activity by acetyl-boswellic Acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo. J Biol Chem 2005; 280:6170-6180

48) Schmidt C, Cornelia Loos, Lu Jin, Michael Schmiech, Christoph Q. Schmidt, Menna El Gaafary, Tatiana Syrovets, Thomas Simmet. Acetyl-lupeolic acid inhibits Akt signaling and induces apoptosis in chemoresistant prostate cancer cells in vitro and in vivo Oncotarget
2017; 8(33):55147-55161.

49) Pang, Xiufeng, et al. “Acetyl-11-keto-β-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2–mediated angiogenesis.” Cancer research 69.14 (2009): 5893-5900.

50) Lu, Min, et al. “Acetyl-keto-β-Boswellic acid induces apoptosis through a death receptor 5–mediated pathway in prostate cancer cells.” Cancer research 68.4 (2008): 1180-1186.

p 231 Solomon’s Seal The Mechanism of Action—Blocks EGFR in Prostate CA

Perhaps the most elucidating study on the mechanism of action of PCL is the 2017 study
by Dr. Hong Zhang et al. using a prostate cancer cell line. In prostate cancer, hexokinase 2 and the Warburg effect are markedly upregulated, and both are effectively suppressed by PCL. Dr. Zhang’s group then investigated the interaction of PCL with epidermal growth factor (EGF) using Western blot analysis, and found that PCL blocked the active site on the EGF-receptor by competitive binding. The inactivation of EGF blocks activation of the PI3K/Akt downstream pathway, which inhibits glucose consumption, lactate production, and HK2 expression, thus inhibiting the Warburg effect. This same mechanism, they found, holds true for most cancer cells:

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
EGFR/PI3K/Akt [mTOR] activation constitutes a hallmark of most cancer cells and
plays an important role in tumor genesis and progression. (5)

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

5) Zhang, Hong, et al. “Lectin PCL inhibits the Warburg effect of PC3 cells by combining with EGFR and inhibiting HK2.” Oncology reports 37.3 (2017): 1765-1771

Solomon’s Seal and TME in Prostate Cancer

p 233 Solomon’s seal (Polygonatum odoratum and Polygonatum cyrtonema) has been studied and is effective in these cell types:

• Prostate cancer (CAFs = Cancer Associated Fibroblasts) (16)

16) Han, Shu-Yu, et al. “Polysaccharide from Polygonatum Inhibits the Proliferation of Prostate Cancer-Associated Fibroblasts Cells.” Asian Pacific Journal of Cancer Prevention 17.8 (2016): 3829-3833

p 234 Quercetin for prostate cancer

8) Bhat, Firdous Ahmad, et al. “Quercetin reverses EGF-induced epithelial to mesenchymal transition and invasiveness in prostate cancer (PC-3) cell line via EGFR/PI3K/Akt pathway.” The Journal of Nutritional Biochemistry 25.11 (2014): 1132-1139

p 238 Cannabinoids for Prostate Cancer

• Prostate cancer (24)

24) Ruiz, Lidia, Alberto Miguel, and Inés Dıá z-Laviada. “Δ9‐Tetrahydrocannabinol induces apoptosis in human prostate PC‐3 cells via a receptor‐independent mechanism.” FEBS letters 458.3 (1999): 400-404.

p 295 Niclosamide Degrades the LRP6 CoReceptor at One Micromolar- Prostae and Breast Cancer

In 2011, Dr. Lu found that niclosamide inhibited the Wnt pathway by targeting the LRP6-
Wnt co-receptor on the cancer cell surface, degrading the LRP6 protein. This was found at
low concentrations of the drug with IC50 values less than 1 micromolar for prostate and
breast cancer cells. (5)

5) Lu, Wenyan, et al. “Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway.” PloS one 6.12 (2011): e29290.

Niclosamide Prostate Cancer-Blocks Antegrade Trafficking in Prostate Cancer Cell Line – High Thruput Screening

In 2016, Dr. Magdalena Circu et al., working with a prostate cancer cell line, used a high-content imaging system to screen 2,210 repurposed and natural products for “antegrade lysosome trafficking inhibition” (i.e., perinuclear perinuclear clustering), identifying niclosamide as the best candidate. The mechanism has to do with action on lysosomal pH. Lysosomal acidity is lost, and instead, the acid is released into the cytosol. (8–9)

8) Circu, Magdalena L., et al. “A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion.” PLoS ONE 11.1 (2016).

9) Circu, Magdalena L., et al. “Correction: A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion.” PloS one 11.3 (2016).

p 309 Niclosamide Potent STAT 3 Inhibitor

Previous high-throughput screening using adrenocortical carcinoma and prostate cancer
cells identified niclosamide as a potent STAT3 inhibitor

Niclosamide for Prostate cancer (8)(64)

64) Sobhani, Navid, et al. “Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate- resistant prostate-cancer.” Investigational new
drugs 36.6 (2018): 1133-1137

Mebendazole Synergy with oncology drugs and radiation in Prostate Cancer:

Synergy with Docetaxel for prostate cancer (16)

16) Rushworth, Linda K., et al. “Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment.” British Journal of Cancer (2019): 1-11.

p 320 Fenbendazole is effective in other cell types, including:

• Prostate cancer (64)

64) Aycock-Williams, Ari N., et al. “Effects of fenbendazole and vitamin E succinate on the growth and survival of prostate cancer cells.” J Cancer Res Exp Oncol 3.9 (2011): 115-121.

p 320 Oxibendazole is effective for:
• Prostate cancer (75)

75) Chen, Qiaoli, et al. “Oxibendazole inhibits prostate cancer cell growth.” Oncology Letters 15.2 (2018): 2218-2226.

p 361 Case Report: Dramatic Response to AHCC in Prostate Cancer

In 2009, Dr. Jeffrey Turner published a case report of a 66-year-old male with castration-resistant prostate cancer (CR-PC). The patient initially presented to the hospital with a two month history of left hip pain and 12-pound weight loss. MRI imaging showed blastic metastatic disease of the lumbar spine. (Blastic means the lesions are “white” on X-ray and CAT scan, meaning dense calcified lesions typical for prostate cancer).
The initial PSA was quite elevated at 2,000. (Normal is less than 4.0) Biopsy showed prostate cancer and treatment with androgen blockade with leuprolide and bicalutamide produced an initial decline in PSA to 993 ng/ml/, and 4 months later further declined to 2.5 (normal). Unfortunately, the remission was temporary, with gradually increasing PSA reaching 30.0 about 8 months later. About 10 months later, androgen blockade had been withdrawn, and the PSA had risen to 69.3. About this time, after withdrawal of all medical treatment, the patient began self-treatment with AHCC mushroom supplement, and the PSA after one month on the mushroom extract had dropped to 3.34 and later to 1.5 ng/ml. The patient’s metastatic bone disease remained stable on repeat imaging, and ambulation improved with alleviation of bone pain. (35)

35) Turner, Jeffrey, and Uzair Chaudhary. “Dramatic prostate-specific antigen response with activated hemicellulose compound in metastatic castration-resistant prostate cancer.” Anti-cancer drugs 20.3 (2009): 215-216.

Iodine for Prostate cancer (39)

39) 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.

p 301 Selenium

133) Cui, Jinling, et al. “Inorganic Selenium Induces Nonapoptotic Programmed Cell Death in PC-3 Prostate Cancer Cells Associated with Inhibition of Glycolysis.” Journal of Agricultural and Food Chemistry 67.38 (2019): 10637-10645.

p 392 Mefloquine Prostate cancer (31–32)

31) Yan, Kun-Huang, et al. “Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo.” Oncology letters 5.5
(2013): 1567-1571.

32) Yan, Kun-Huang, et al. “Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling.” Oncology letters 5.5 (2013): 1541-1545.

Mefloquine Anti-Cancer Blood Levels Prostate CA Model

In 2013, Dr. Kun-Huang Yan et al. studied mefloquine (MQ) in a prostate cancer cell
model, finding that mefloquine had highly selective anti-cancer activities. Although prostate
cancer cells were sensitive to the cytotoxic effects of MQ at 10 micromolar, other normal
cells such as fibroblasts were unaffected. Dr. Yan’s group noted that mefloquine blood levels
in the 2.1–23 micromolar range are typically found with antimalaria therapy, while
blood levels in the 3–4 micromolar range are found with malaria prophylaxis for travelers.
This can be compared to the 4–10 micromolar range found effective for cancer treatment in
Dr. Sukhai’s in vitro leukemia cell study. (24) (32)

24) Sukhai, Mahadeo A., et al. “Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” The Journal of clinical investigation 123.1
(2013): 315-328.

p 404 D3 for prostate

Dr. Yu and colleagues write:
Calcitriol causes antiproliferative effects through multiple mechanisms, including
the induction of cell cycle arrest, apoptosis and differentiation in vitro and in vivo in
a variety of cancer cell types including prostate, breast, colon, skin and leukemic
cells. (19)

19) Yu, Wei-Dong, et al. “Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system.” Cell cycle 9.15 (2010): 3094-3101.

p 409 Chloroquine Synergy with Sulforaphane

In 2013, Dr. Vyas reported sulforaphane and chloroquine had synergistic effects in prostate
cancer chemoprevention. (88)

88) Vyas, Avani R., et al. “Augmentation of D, L-sulforaphane-mediated prostate cancer chemoprevention by pharmacologic inhibition of autophagy using chloroquine in a transgenic mouse model.” Cancer Research 73.8 Supplement (2013): 3695-3695.

p 410 Autophagy Inhibitors—Propranolol

In 2018, Dr. Laura Brohée et al. studied prostate cancer cells in vitro and in vivo, using a
combination treatment of glycolysis inhibitor (2DG) and autophagy inhibitor (propranolol),
finding that:

the blockage by propranolol of the autophagy flux induced by 2DG resulted
in a strong accumulation of LC3-II and p62 [autophagy marker proteins] and in
a massive accumulation of autophagic vesicles … due to autophagy blockade. The
propranolol + 2DG treatment efficiently prevents prostate cancer cell proliferation,
induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics
and aggravates ER [endoplasmic reticulum] stress in vitro and also suppresses
tumor growth in vivo. (107)

107) Brohée, Laura, et al. “Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.” Scientific reports 8.1
(2018): 1-14.

p 421 In Vivo Studies PPI Drugs Enhance Chemotherapy

In 2015, Dr. Tan et al. studied the PPI drug pantoprazole, added to the chemotherapy
agent docetaxol, against three cancer cell lines (breast, prostate, and epidermoid skin cancer) as mouse xenografts, finding dramatic enhancement of docetaxol activity by the PPI
drug.

Note: docetaxol is a taxane microtubule agent. This was further studied and found to
be due to autophagy inhibition by the PPI drug. Similar to many other chemotherapy drugs,
docetaxol upregulates “protective autophagy” which promotes survival in cancer cells.
Inhibition of “protective autophagy” with a PPI drug is confirmed by finding increased protein
markers LC3-II and p62. Dr. Tan and colleagues write:

Our results suggest that pantoprazole inhibits autophagy by raising lysosomal
pH and/or by inhibiting fusion of autophagosomes with lysosomes, leading to
the accumulation of autophagosomes…. pantoprazole increased the accumulation
of both LC3-II and p62. (30–32)

p 422 Devising a More Robust Protocol for Prostate Cancer

A more robust drug combination program for prostate cancer would include:
• DCA (plus poly-MVA) or diclofenac- glycolysis inhibitor.
• Daily oral PPI drug such as pantoprazole as autophagy inhibitor. A second lysosomal agent, loratadine 10 mg/day might also be added.
• Fenofibrate dual OXPHOS and Glycolysis inhibitor, 400 mg per day with evening meal. Use in Combination with vitamin A 25-50,000 iu/d (or derivative)
• Propranolol OXPHOS and autophagy inhibitor (80 mg per day) or
Niclosamide (dual OXPHOS/autophagy inhibitor)
• Sulforaphane (broccoli extract) depletes glutathione and is synergistic with autophagy inhibitors, eradicates CSCs. Sulforaphane was discussed in the chapter 10 on natural substances targeting CSCs.
• Other supplements such as melatonin, thymoquinone, curcumin, boswellia, pterostilbene, iodine, poly-MVA (alpha lipoic and thiamine) etc.

Also add Metformin

Zaidi, Saher, et al. “The anticancer potential of metformin on prostate cancer.” Prostate cancer and prostatic diseases 22.3 (2019): 351-361.

Spratt, Daniel E., et al. “Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.” European urology 63.4 (2013): 709-716.

p 426 Dipyridamole as Autophagy Inhibitor

The old antiplatelet drug dipyridamole is discussed in chapter 40, and should be mentioned
here as another autophagy inhibitor, as reported by Dr. Marcos P. Thomé et al. (2018) in a prostate cancer cell model. Thomé found that treatment of cancer cells resulted in an increased number of autophagosomes and autolysosomes, indicating blockage of autophagic flux, thought to be secondary to increased intracellular cAMP
(cyclic AMP).(73-74)

73) Thomé, Marcos P., et al. “Dipyridamole impairs autophagic flux and exerts antiproliferative activity on prostate cancer cells.” Experimental cell research
382.1 (2019): 111456.

p 438 Thymoquinome Prostate cancer (70–72)

70) Singh, Santosh Kumar, et al. “Docetaxel Combined with Thymoquinone Induces Apoptosis in Prostate Cancer Cells via Inhibition of the PI3K/AKT Signaling Pathway.” Cancers 11.9 (2019): 1390.

71) Saffari Chaleshtori, Javad, et al. “The Effects of Thymoquinone on Viability, and Anti-apoptotic Factors (BCL-XL, BCL-2, MCL-1) in Prostate Cancer (PC3) Cells:
An In Vitro and Computer-Simulated Environment Study.” Advanced pharmaceutical bulletin 9.3 (2019): 490.

72) Ranjbari, Azadeh, Esfandiar Heidarian, and Keihan Ghatreh-Samani. “Effects of thymoquinone on IL-6 Gene expression and some cellular signaling pathways
in prostate cancer PC3 cells.” Jundishapur Journal of Natural Pharmaceutical Products 12.3 (2017).

p 455 Itraconazole for Prostate Cancer

p 455 Itraconazole has been in clinical use for 30 years with an established safety record.
Multiple phase 2 clinical trials investigating itraconazole for non-small-cell lung cancer,
prostate cancer, and basal cell carcinoma have been completed, showing an increase in progression-free and overall survival. (3–7)

5) Tsubamoto, Hiroshi, et al. “Repurposing itraconazole as an anticancer agent.” Oncology Letters 14.2 (2017): 1240-1246.

p 458 Prostate Cancer Clinical Trial

A 2013 clinical trial was published by Dr. Emmanuel Antonarakis et al. in the Oncologist
using itraconazole in men with metastatic castration-resistant prostate cancer. Forty six
men were randomized to receive either a low dose, 200 mg per day, or high-dose, 600 mg per day of itraconazole. Progression-free survival was determined by PSA. The progression-free survival for the high-dose group was 4 times greater than the low-dose group.

The PFS [progression-free survival] rates at 24 weeks were 11.8% in the low-dose
arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9
weeks.(10)
Fifty percent of the men remained progression- free for 6 months on the 600 mg per day
itraconazole.

10) Antonarakis, Emmanuel S., et al. “Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer.” The oncologist 18.2 (2013): 163-173.

p 458 Phase Two Clinical Trial in Prostate Cancer

In a 2019 phase two clinical trial by Dr. Mina Lee et al. for recurrent prostate cancer, nineteen men were given itraconazole 300 mg orally twice a day for 12 weeks. Of the 19, one had a greater than 50% reduction in PSA. Nine others had a (median) 25% reduction in PSA after 12 weeks of itraconazole. Adverse effects were related to mineralocorticoid effects of itraconazole with edema and hypertension. (11)

11) Lee, Mina, et al. “Itraconazole as a noncastrating treatment for biochemically recurrent prostate cancer: a phase 2 study.” Clinical genitourinary cancer 17.1
(2019): e92-e96.

p 480 Fenofibrate for Prostate cancer (42–48)

42) Luty, Marcin, et al. “Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel.” Cancers 11.1 (2019): 77.

43) Lian, Xin, et al. “Fenofibrate inhibits mTOR-p70S6K signaling and simultaneously induces cell death in human prostate cancer cells.” Biochemical and biophysical
research communications 496.1 (2018): 70-75.

44) Wybieralska, Ewa, et al. “Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations.” Oncology reports 26.2 (2011): 447-453

45) Wróbel, T., et al. “1947P Fenofibrate impairs pro-tumorigenic potential of cancer stem cell-like cells within drug-resistant prostate cancer cell populations.” Annals of Oncology 30. Supplement 5 (2019): 268-074.

46) Tao, Tao, et al. “Fenofibrate inhibits the growth of prostate cancer through regulating autophagy and endoplasmic reticulum stress.” Biochemical and biophysical research communications 503.4 (2018): 2685-2689.

47) Lian, Xin, et al. “Fenofibrate inhibits mTOR-p70S6K signaling and simultaneously induces cell death in human prostate cancer cells.” Biochemical and biophysical
research communications 496.1 (2018): 70-75.

48) Wróbel, T., et al. “1947P Fenofibrate impairs pro-tumorigenic potential of cancer stem cell-like cells within drug-resistant prostate cancer cell populations.” Annals of Oncology 30.Supplement_5 (2019): mdz268-074.

Celecoxib COX 2 Inhibitor for Prostate CAncer

Synergy with Statin

In 2000, Dr. Ao-Lin Hsu et al. studied a prostate cancer-cell model, finding:

celecoxib induces apoptosis by blocking Akt [PI3K/Akt pathway] activation in
human prostate cancer cells independently of Bcl-2 … inhibition of Akt activation
may play a crucial role in the induction of apoptosis by celecoxib. (34)
Note: PI3K-Akt Pathway is a growth survival pathway for cancer cells.

19) Huang, Huarong, et al. “Combination of Lipitor and Celebrex inhibits prostate cancer VCaP cells in vitro and in vivo.” Anticancer research 34.7 (2014): 3357-3363.

34) Hsu, Ao-Lin, et al. “The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2.” Journal of Biological Chemistry 275.15 (2000): 11397-11403.

p 501 DIM for prostate cancer

70) Li, Yiwei, Sreenivasa R. Chinni, and Fazlul H. Sarkar. “Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells.” Front Biosci 10 (2005): 236-243.

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): 1-18.

p 534 Prostate Cancer Tocotrienol vitamin E

Tocotrienol is only one of many natural compounds targeting prostate cancer discussed by Dr. Fontana in 2020, writing:

Among these naturally occurring molecules, quercetin, fisetin, luteolin, apigenin,
curcumin, resveratrol, genistein, silibinin, kaempferol, epigallocatechin-3-gallate
[EGCG], tocotrienols, sulforaphane, ginsenosides, ursolic acid, berberine, honokiol,
xanthoumol, oridonin, and tannic acid have shown outstanding potential as anti-PCa
[anti-prostate cancer] agents in in vitro and preclinical experiments. (7-9)

Dr. Fontana found that Delta Tocotrienol impaired mitochondrial respiration, induced
apoptosis and endoplasmic stress which induced “protective autophagy” in prostate
cancer cell models. (7-9)

7) Fontana, Fabrizio, et al. “Natural compounds in prostate cancer prevention and treatment: mechanisms of action and molecular targets.” Cells 9.2 (2020): 460.

8) Fontana, Fabrizio, et al. “Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells.” Free Radical Biology and Medicine (2020).

9) Fontana, Fabrizio, et al. “δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells.” Cell proliferation 52.3 (2019): e12576.

p 534 Prostate Cancer Tocotrienol

Tocotrienol vitamin E is only one of many natural compounds targeting prostate cancer
discussed by Dr. Fontana in 2020, writing:

Among these naturally occurring molecules, quercetin, fisetin, luteolin, apigenin,
curcumin, resveratrol, genistein, silibinin, kaempferol, epigallocatechin-3-gallate
[EGCG], tocotrienols, sulforaphane, ginsenosides, ursolic acid, berberine, honokiol,
xanthoumol, oridonin, and tannic acid have shown outstanding potential as anti-PCa
[anti-prostate cancer] agents in in vitro and preclinical experiments. (7-9)

Dr. Fontana found that Delta Tocotrienol impaired mitochondrial respiration, induced
apoptosis and endoplasmic stress which induced “protective autophagy” in prostate
cancer cell models. (7-9)

7) Fontana, Fabrizio, et al. “Natural compounds in prostate cancer prevention and treatment: mechanisms of action and molecular targets.” Cells 9.2 (2020): 460.

10) Tang, Kai Dun, et al. “Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway.” International journal of molecular sciences 20.5 (2019): 1164.

11) Huang, Ying, et al. “A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27.” The Journal of Nutritional Biochemistry 40 (2017): 155-163.

Synergy with Docetaxel Chemotherapy in Prostate Cancer

12) Asay, Spencer, et al. “γ‐Tocotrienol and α‐Tocopheryloxyacetic Acid Increase the Effectiveness of Docetaxel Treatment of PC‐3 Prostate Cancer Cells and Docetaxel‐resistant PC‐3 Cells.” The FASEB Journal 33.S1 (2019): 647-2.

Tocotrienol/Metformin Synergy

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

35) 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

Silymarin p 579

153) Delmas, Dominique, et al. “Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity.” Molecules 25.9 (2020): 2009.

154) Kacar, Sedat, Nuriye Ezgi Bektur Aykanat, and Varol Sahinturk. “Silymarin inhibited DU145 cells by activating SLIT2 protein and suppressing expression of CXCR4.” Medical Oncology 37.3 (2020): 1-9.

155) Snima, K. S., et al. “Silymarin encapsulated poly (D, L-lactic-co-glycolic acid) nanoparticles: a prospective candidate for prostate cancer therapy.” Journal
of biomedical nanotechnology 10.4 (2014): 559-570.

p 478

Fenobifrate (FASN inhibitor ) combined with microtubule agent

fenofibrate plus mebendazole ?

The studies by Dr. Heuer’s group found
enhanced synergy both in vitro and in vivo
when FASN inhibitors (TVB-3166 and 3664)
were combined with taxane drugs. Dr. Heuer
et al. write that the combination of FASN inhibition
and a taxane drug:

demonstrate significantly enhanced
anti-tumor efficacy when FASN inhibition
is combined with paclitaxel or docetaxel
in vitro and in vivo … Impressively, the
effects include induction of near complete
tumor regression in a variety of diverse
tumor cell-line-and patient-derived tumor
models that include lung, ovarian, pancreatic,
and prostate tumor models …
Together, these results provide compelling
mechanism- and efficacy-based evidence
for combined FASN and taxane therapy as
a cancer therapy. (34)

34) Heuer, Timothy S., et al. “FASN inhibition and taxane
treatment combine to enhance anti-tumor efficacy
in diverse xenograft tumor models through disruption
of tubulin palmitoylation and microtubule organization
and FASN inhibition-mediated effects on oncogenic
signaling and gene expression.” EBioMedicine
16 (2017): 51-62.

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Not In Book- Extra

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Veratramine found to inhibit androgen-independent prostate cancer
by Daegu Gyeongbuk Institute of Science and Technology (DGIST) Medical Xpress
Sept 2023.

Veratramine extracted from Veratrum japonicum, a wild island plant, has been known to inhibit the proliferation of liver cancer and brain neuroglioma cells and is also effective for high blood pressure and inflammatory diseases. However, the effect of veratramine on prostate cancer had not been studied before.

The research team led by Choi Seong-gyun applied veratramine to prostate cancer cells and identified the concentration at which it inhibits the cells’ biological functions. They confirmed that veratramine significantly inhibits the proliferation of prostate cancer.

free pdf

Kim, Hee-Yeon, et al. “Veratramine Inhibits the Cell Cycle Progression, Migration, and Invasion via ATM/ATR Pathway in Androgen-Independent Prostate Cancer.” The American Journal of Chinese Medicine 51.05 (2023): 1309-1333.

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Fenbendazole and Albendazole

Chung, Ivy, et al. “Unbiased phenotype-based screen identifies therapeutic agents selective for metastatic prostate cancer.” Frontiers in Oncology 10 (2020).

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.

Jeffrey Dach MD

Bioidentical Hormones Natural Thyroid

Index for Prostate Cancer