Doxycycline Vitamin C Anti Cancer Synergy

Doxycycline Vitamin C AnticancerDoxycycline Vitamin C Anti-Cancer Synergy

Eradicates Cancer Stem Cells

I was simply astounded by a publication appearing last week in Oncotarget  on anti-cancer synergy of Doxycyline and vitamin C.(1)  This is a really huge breakthrough in cancer research,  in our quest for effective non-toxic cancer treatment.  Working with MCF7 Breast cancer cell cultures, Lisanti’s group showed  the combined use of Doxycycline and Vitamin C  was a “lethal metabolic strategy for eradicating cancer stem cells”.(1)

Doxycycline

DoxycyclineDoxycline is a safe common antibiotic used for 50 years. I have seen patients coming into the office  on doxycycline for months  or even years for treatment of acne or rosacea.  Likewise Vitamin  C is about as safe as a substance as you can get.  Clinical trial safety study on relapsed B-Cell Lymphoma patients receiving 75 grams of Vitamin C Intravenously reported no adverse effects.(47)  Left image doxycycline courtesy of National Library of Medicine

Cancer Stem Cells Escape from Doxycycline Become Purely Glycolytic Phenotype

In an elegant study, Lisanti’s group created Doxycycline resistant cancer stem cells by successive passage of the cells through higher doses of Doxycycline treatments.   Most of the cells were killed by the Doxycycline.  However the few surviving cells were then allowed to multiply and repopulate, and were again treated with higher doses of doxyxycline.  This process was repeated until final cells were indeed Doxycyline resistant, they were immune to the antibiotic.

Vitamin C Doxycycline FIG 12 zzLisanti’s group then did next generation molecular studies on the Dox-R cancer stem cells showing they had assumed a purely glycolytic phenotype.

Above left image Figure 12 from Lisanti (1)

The Dox-Resistant cancer cells were now sensitive to eradication with metabolic perturbation from high dose vitamin C.  Vitamin C acts as a glycolysis inhibitor, by targeting (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase, 6th step in glycolysis.   Vitamin C also and depletes the (NAD) nicotinamide adenine dinucleotide pool.  High dose IV vitamin C easily reached serum concentrations for these lethal effects in the clinical setting.

A few other drugs and natural substances were also effective, namely Berberine, Chloroquin, Atovaquone (45-46), Niclosamide etc. )  The authors state, “understanding the metabolic basis of Doxycycline-resistance has ultimately helped us to develop a new synthetic lethal strategy, for more effectively targeting Cancer Stem Cells (CSCs). ” 

Ascorbic Acid Vitamin C and Doxycycline Kills Cancer Stem CellsLeft Image figure 10 from Lisanti(1)  Fig A effect of 2DG (2-de-oxyglucose) on both plain MC7 breast cancer stem cells and Dox-resistant cells.  Fig B: effect of Vitamin C on Dox Resistant breast cancer stem cells.  100% (complete) cell death at 500 micromolar=0.5 millimolar.

Metformin and Cancer Stem Cells

Lisanti’s group found Berberine effective against cancer stem cells.  Metformin is another agent with similarities to berberine which targets cancer stem cells by inhibiting Complex One in the mitochondrial electron transport chain.  Working with a pancreatic cancer cell model, Dr Patricia Sanchez in Cell Metabolism 2015 found that Metformin was effective as a cancer stem cell agent. (44) Dr Sanchez found that cancer stem cells rely on OXPHOS (oxidative Phosphorylation) while non-cancer stem cells were highly glycolytic. (44)  Metformin treatment killed most of the cancer stem cells.  However resistant stem cell clones emerged with a glycolytic phenotype.  As noted above, this conversion to a glycolytic phenotype is exactly what Lisanti’s group found when treating breast cancer stem cells with Doxycyline.   This glycolytic phenotype was then vulnerable to lethal effects of  high dose IV vitamin C serving as glycolysis inhibitor.

Dr Sanchez was disappointed to find that pancreatic tumors developed resistance to Metformin progressed in a more aggressive form in cancer xenografts.  On the other hand, treatment with Menadione (Vit K3), which both inhibited complex one and increased ROS, was lethal to the cancer xenografts without inducing resistant cell types.

Salinomycin 3BP Bogata Colombia

Salinomycin, another promising cancer stem cell agent, was used in an anecdotal case report from Bogata Colombia by Jason Williams MD and Marc Rosenberg MD.  Twenty One rounds of IV Salinomycin and 3-bromopyruvate was given on alternate days to a patient with small cell lung cancer.  Follow up  CAT scan showed disappearance of the patient’s lung mass.  Although results were encouraging, further Salinomycin trials in 20 or so additional patients provided only temporary remission from cancer, with later emergence of resistant cell types.(personal communication Jason Williams MD)   Following these disappointing results, research efforts were re-directed towards other modalities such as image guided ablation and immunotherapy.   Perhaps results would have been better with the use of other combination drugs such as Doxycycline, High Dose IV Vitamin C, Metformin, Atovaquone, Artesunate, Alpha Lipoic Acid  etc.

This highlights the dangers of Cancer Stem Cell treatments which merely induce resistant cancer cell types which are more aggressive and more difficult to treat.  Another problem is knowing when the treatment has eradicated all the cancer stem cells.  At the present time we don’t have a good method for determine this, and so we don’t know when to stop treatment.   If treatment is stopped too soon, then resistant cancer stem cells are left behind to induce a relapse.  This is a major problem which awaits further research. This will be discussed in part two.

Lisanti Lamb Doxycycline Ascorbate Atovaquone Cancer Stem Cells Fig 9Left Image Figure 9 from Lisanti. (1)

Dr Lisanti’s group found that Doxycyline combination therapy for eradication of cancer stem cells worked with other drugs such as the OXPHOS inhibitor, Atovaquone, an anti-malaria drug which inhibits complex III of the mitochondrial electron transport chain.(1)  Atavaquone is already FDA approved for prevention of Pneumocyctis pneumonia in immunosuppressed patients, and easily reaches effective serum levels with routine dosage of 750 mg BID with food.(45-46)

Ignoring the Cancer Stem Cells – the Failure of Oncology

For rapidly proliferating cancer cell types chemotherapy will provide a temporary remission, or reduction in tumor size.  However, cancer stem cells are unaffected by chemotherapy and will induce cancer relapse.  The more aggressive, highly  proliferative cell types relapse within months while the more indolent cell types take longer, and relapse after a few years.  Clearly, targeting cancer stem cells is imperative in order to prevent cancer relapse after treatment.  Unfortunately, current day oncology has failed the cancer patient by ignoring cancer stem cells, and blindly forging ahead with the old chemotherapy protocols, as if medical science is still in the 1960’s, and nothing has changed.

Conclusion: My hat comes off in admiration and thanks to Michael Lisanti and his group.  This Doxycycline/ Vitamin C combination is a dramatic breakthrough in finding an effective targeted cancer stem cell eradication strategy.  Hopefully, this technique will be incorporated and routinely used on the oncology wards. In the mean time, print out this article and give it to your oncologist.  Ask for and demand the hospital provide Doxyxycline and IV high dose vitamin C for your family members undergoing chemotherapy for cancer.

This article is part one.  For part two click here.

Articles with related interest:

Targeting Cancer Stem cells with Non-Toxic Therapies

Intravenous Vitamin C as Cancer Chemotherapy

Cancer Immune System Evasion with PIBF

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

References

1) De Francesco, E. M., Michael Lisanti et al. “Vitamin C and Doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).” Oncotarget (2017). Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).

2) Combining vitamin C with antibiotics destroys cancer stem cells
By Honor Whiteman  published Tuesday 13 June 2017 670

3) Vitamin C and Antibiotic Combo Can Kill Cancer Cells
Posted on June 13, 2017, 6 a.m. in Cancer Immune System Vitamins
Researchers have shown that a combination of antibiotics and Vitamin C can destroy cancer stem cells before they promote the growth of fatal tumors.

4) Antibiotics and vitamin C could kill cancer cells

Doxycyline Effective for B Cell Lymphoma

5) Pulvino, Mary, et al. “Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline.
In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

nice image

6) Barbie, David A., and Brian K. Kennedy. “Doxycycline: new tricks for an old drug.” Oncotarget 6.23 (2015): 19336.

also images
7) Peiris-Pagès, Maria, Federica Sotgia, and Michael P. Lisanti. “Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose.” Oncoscience 2.8 (2015): 696.

8) free pdf
Saikali, Zeina, and Gurmit Singh. “Doxycycline and other tetracyclines in the treatment of bone metastasis.” Anti-cancer drugs 14.10 (2003): 773-778.

9) Onoda, Toshinao, et al. “Tetracycline analogues (doxycycline and COL‐3) induce caspase‐dependent and‐independent apoptosis in human colon cancer cells.” International journal of cancer 118.5 (2006): 1309-1315.

10) Iwasaki, Hiromichi, et al. “Doxycycline induces apoptosis by way of caspase-3 activation with inhibition of matrix metalloproteinase in human T-lymphoblastic leukemia CCRF-CEM cells.” Journal of Laboratory and Clinical Medicine 140.6 (2002): 382-386.

11) Sun, Tao, et al. “Doxycycline inhibits the adhesion and migration of melanoma cells by inhibiting the expression and phosphorylation of focal adhesion kinase (FAK).” Cancer letters 285.2 (2009): 141-150.

12) Lokeshwar, Bal L. “Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers.” Pharmacological research 63.2 (2011): 146-150.

Breast Cancer

13) Zhang, Le, et al. “Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer.” Cell Cycle just-accepted (2016): 00-00.

14) Tang, Xiaoyun, et al. “Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-κB activation.” Molecular cancer 16.1 (2017): 36.

Doxycycline suppressed both LPA- and TNFα-induced nuclear translocation of NF-κB and blocked the LPA-induced secretion of IL-6, CCL2 and CXCL2 in cancer cells. TNFα-induced nuclear NF-κB transcriptional activity was also inhibited by doxycycline. Under basal condition without stimulation, doxycycline was able to decrease the transcriptional activity of nuclear NF-κB by ~50%

The equivalent dose for human is ~4 mg/kg/day calculated by equivalent surface area dosage conversion factor, which is 240 mg/day for 60 kg of body weight. The typical dose of doxycycline is 100–200 mg/day and the maximum dose is 300 mg/day for more serious infections, such as syphilis.

15) Fife, Rose S., and George W. Sledge Jr. “Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells.” The Journal of laboratory and clinical medicine 125.3 (1995): 407-411.

16) Rubins, Jeffrey B., et al. “Inhibition of mesothelioma cell growth in vitro by doxycycline.” Journal of Laboratory and Clinical Medicine 138.2 (2001): 101-106.

17) Shen, Ling-Chang, et al. “Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma–in vitro and in vivo studies.” Oral oncology 46.3 (2010): 178-184.

18) Wang-Gillam, Andrea, et al. “Anti-tumor effect of doxycycline on glioblastoma cells.” Journal of Cancer Molecules 3.5 (2007): 147-153.Anti-Tumor Effect of Doxycycline on Glioblastoma Cells

19) Tolomeo, Manlio, et al. “Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines.” British journal of pharmacology 133.2 (2001): 306-314.

20) Liu, Jian, Charles A. Kuszynski, and B. Timothy Baxter. “Doxycycline induces Fas/Fas ligand-mediated apoptosis in Jurkat T lymphocytes.” Biochemical and biophysical research communications 260.2 (1999): 562-567.

21) Onoda, Toshinao, et al. “Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells.” Journal of Laboratory and Clinical Medicine 143.4 (2004): 207-216.

22) Fife, Rose S., et al. “Effects of tetracyclines on angiogenesis in vitro.” Cancer letters 153.1 (2000): 75-78.

23) Sagar, Jayesh, et al. “Doxycycline in mitochondrial mediated pathway of apoptosis: a systematic review.” Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 10.7 (2010): 556-563.

24) Richards, Christopher, Liron Pantanowitz, and Bruce J. Dezube. “Antimicrobial and non-antimicrobial tetracyclines in human cancer trials.” Pharmacological research 63.2 (2011): 151-156.

25) van den Bogert, Coby, et al. “Arrest of the proliferation of renal and prostate carcinomas of human origin by inhibition of mitochondrial protein synthesis.” Cancer research 46.7 (1986): 3283-3289.

26) Kroon, Albert M., et al. “The mitochondrial genetic system as a target for chemotherapy: tetracyclines as cytostatics.” Cancer letters 25.1 (1984): 33-40.

27) van den Bogert, Coby, Bert HJ Dontje, and Albert M. Kroon. “The antitumour effect of doxycycline on a T-cell leukaemia in the rat.” Leukemia research 9.5 (1985): 617-623.

Antibiotics Eradicate Cancer Stem Cells

2015 OncoTarget

28) Lamb, Rebecca, et al. “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease.”  Lamb Rebecca Antibiotics that target mitochondria effectively eradicate cancer stem cells 2015 OncoTarget  Lamb Rebecca Antibiotics that target mitochondria effectively eradicate cancer stem cells 2015 OncoTarget

Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

Doxycycline for Lymphoma

2015
29) Ann Hematol. 2015 Apr;94(4):575-81. Long-term outcomes of first-line treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell lymphoma. .  Han JJ1, Kim TM, Jeon YK, Kim MK, Khwarg SI, Kim CW, Kim IH, Heo DS.
Author information 1Department of Internal Medicine, Seoul National University Hospital, 101  Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.

Ocular adnexal lymphoma (OAL) has been associated with Chlamydophila psittaci infection, for which  doxycycline has been suggested as a treatment option. We conducted this study to evaluate the long-term results of first-line doxycycline treatment in patients with OAL. Ninety patients withhistologically confirmed OAL with marginal zone B cell lymphoma were enrolled. Each patient received one or two cycles of doxycycline (100 mg bid) for 3 weeks. After a median follow-up period of 40.5 months (8-85), the 5-year progression-free survival (PFS) rate was 60.9 %. All patients were alive at the last follow-up date. Thirty-one patients (34 %) showed local treatment failure without systemic spread. However, PFS rate in these patients was 100 % after salvage chemotherapy and/or radiotherapy.

PFS was independently predicted in multivariate analysis by the tumor-node-metastasis (TNM) staging (hazard ratio [HR], 4.35; 95 % confidence interval [CI], 2.03-9.32; P < 0.001) and number of cycles of doxycycline (HR, 0.31; 95 % CI, 0.14-0.69; P = 0.004). No serious adverse event was reported during doxycycline therapy. In conclusion, first-line doxycycline therapy was effective and safe.

Patients who failed to respond to doxycycline therapy were successfully salvaged with chemotherapy and/or radiotherapy without compromising long-term outcomes. Patients with T1N0M0 disease could be considered good candidates for first-line doxycycline.

2015

13 patients antibiotics alone for gastric lymphoma – HP eradication regimen

30) Ann Hematol. 2015 Jun;94(6):969-73. doi: 10.1007/s00277-014-2298-3. Epub 2015 Jan 13. Antibiotic treatment as sole management of Helicobacter pylori-negative gastric MALT lymphoma: a single center experience with prolonged follow-up.  Raderer M1, Wöhrer S, Kiesewetter B, Dolak W, Lagler H, Wotherspoon A, Muellauer L, Chott A.

Relatively little is known about the long-term outcome of patients with Helicobacter pylori (HP)-negative gastric lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with antibiotic therapy as sole management. We have analyzed all patients with HP-negative gastric MALT lymphoma undergoing antibiotic therapy as sole management of their disease. HP negativity was defined as negative histology, breath test and serology, and response to treatment, survival and long-term outcome was assessed together with clinico-pathological characteristics including t(11; 18) (q21; q21) translocation. Out of 97 patients with gastric MALT lymphoma, 24 were HP-negative, and 13 (5 females and 8 males) underwent only antibiotic management for initial therapy. Eight had stage I and five were found to have stage II disease, with three patients suffering from an underlying autoimmune disease. Antibiotic therapy consisted of standard HP eradication regimens consisting of clarithromycin in all patients, along with metronidazole in seven and amoxicillin in six plus a proton-pump inhibitor. After a median follow-up of 95 months (42-, 181+), 12/13 patients are alive. Six patients with stage I disease achieved an objective response (five complete (CR) and one partial remission, 46 %), four had stable disease (lasting 11-27 months), and three progressed. All patients with stable disease received chemotherapy, but only one patient due to clear cut progression. One patient relapsed 23 months after initial CR, and achieved a second CR with antibiotics now lasting 87 months. These results indicate that a relevant percentage of patients with HP-negative gastric MALT lymphoma may benefit from antibiotic therapy and do not require additional oncological therapies. Our data suggest that the remissions seen in these patients might be durable as evidenced by prolonged follow-up in our series.

2013

31) Kiesewetter, Barbara, and Markus Raderer. “Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature” Blood 122.8 (2013): 1350-1357.

A single course of oral doxycycline at a dose of 100 mg given twice a day for 3 weeks was the most popular regimen and was used by most investigators.14⇓⇓-17,19⇓⇓-22 By contrast, Kim and coworkers19 added a second course after an interval of 3 weeks for patients with residual eye-related symptoms after the initial cycle. The activity of a 6-month oral application of 500 mg clarithromycin twice a day was assessed in an Italian pilot study,18 assuming potential additional direct anticancer effects of macrolide antibiotics through changes in apoptotic mechanisms of tumor cells. In addition, 1 patient received HP eradication as first-line treatment of OAML.  CR was achieved in 23 patients (18%) out of the collective of all 131 patients reported. Thirty-six (27%) had a PR

2006

32) Ferreri, Andrés JM, et al. “Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial.” Journal of the National Cancer Institute 98.19 (2006):1375-1382.

Background: An association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infection has been proposed, and recent reports suggest that doxycycline treatment causes tumor regression in patients with Cp-related OAL. The effectiveness of doxycycline treatment in Cp-negative OAL has not been tested. Methods: In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were two-sided. Results: Eleven patients were Cp DNA–positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in six patients, and a partial response (≥50% reduction of all measurable lesions) was observed in seven patients (overall response rate [complete and partial responses] = 48%). Lymphoma regression  was observed in both Cp DNA–positive patients (seven of 11 experienced regression) and Cp DNA–negative patients (six of 16 experienced regression) (64% versus 38%; P = .25, Fisher’s exact test). The three patients with regional lymphadenopathies and three of the five patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline- treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. Conclusions: Doxycycline is a fast, safe, and active therapy for Cp DNA–positive OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR-negative OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria.

Ferreri et al conducted a prospective phase 2 clinical trial of 27 patients (15 newly diagnosed and 12 relapsed) with OAML, using doxycycline 100 mg orally twice daily for 3 weeks.  Partial or complete lymphoma regression after antibiotic therapy was observed in 7 of 11 Cp-positive and 6 of 16 Cp-negative patients, with an overall response rate of 48%. The 2-year failure-free survival rate among patients treated with doxycycline was 66%

Abramson et al84 treated 3 patients with biopsy-proven conjunctival MALT lymphoma with antibiotic therapy, resulting in 2 complete remissions and 1 partial response.

Husain et al43 conducted a meta-analysis, identifying 4 studies with a total of 42 patients who had  been treated with oral doxycycline.

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full free pdf
33) Husain, Amina, et al. “Meta–analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics.” Cancer 110.4 (2007): 809-815.

34) Abramson DH, Rollins I, Coleman M. Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Am J Ophthalmol. 2005;140:729–730. Am J Ophthalmol. 2005 Oct;140(4):729-30.

To report on the treatment of primary mucosa-associated lymphoid tumors (MALT)/low grade lymphomas of the conjunctiva/orbit treated solely with systemic antibiotics. DESIGN: Retrospective interventional case series.
METHODS: Three adult patients with biopsy/marker proven MALT lymphomas of the conjunctiva/orbit were treated with systemic antibiotics and followed for signs of local or systemic relapse.
RESULTS: All three patients showed a response to antibiotics based on clinical, ultrasonographic, and MRI/CT imaging studies. Two patients have had complete remissions (42 months follow-up) and one a partial remission (18 months). No systemic relapses have occurred.
CONCLUSION: MALT/low grade lymphomas of the conjunctiva/orbit respond to systemic antibiotic therapy and may have complete remissions.

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35) Chatzispyrou, Iliana A., et al.   “Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research.” Cancer research 75.21 (2015): 4446-4449.

36)  Moullan, Norman, et al. “Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research.” Cell reports 10.10 (2015): 1681-1691.

37)   Oncotarget. 2016 Nov 15; 7(46): 75954–75967.
Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells
Carolina V. Alexander-Savino,1 Matthew S. Hayden,1 Christopher Richardson,2 Jiyong Zhao,3 and Brian Poligone1,4
Doxycycline is an inexpensive and widely used tetracycline, commonly known for its antibiotic properties, that was first synthesized from chlortetracycline in 1967 [21]. Chlortetracycline is the parent structure for all tetracyclines and is naturally found in Streptomyces aureofaciens [22]. Doxycycline’s antibiotic effects come from its ability to bind to the bacterial ribosome’s 30s subunit and inhibit protein synthesis.

38) Toberer F, Hartschuh W, Hadaschik E. Primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma: temporary remission by oral doxycycline. JAMA dermatology. 2013;149:956–959.

Preventing Metastases With Anti-platelet drugs and Anti-Progesterone Drug

39)   Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil.
Wan L, Dong H, Xu H, Ma J, Zhu Y, Lu Y, Wang J, Zhang T, Li T, Xie J, Xu B, Xie F, Gao Y, Shao J, Tu X, Jia L  Oncotarget. 2015 Nov 3; 6(34):35157-72.

We then demonstrated that metapristone (the active mifepristone metabolite) has a safe and effective profile as a cancer metastasis chemopreventive agent by inhibiting adhesion of CTCs to vascular endothelium

Besides, mifepristone significantly decreased expression of focal adhesion kinase that is related to cell spreading and survival. Interestingly, it seems like that there are some similarity between embryo implantation and tumor metastasis [34], which constructs the base for the abortifacient mifepristone to act as a metastatic chemopreventive. Patients already took mifepristone for as long as 14 years [35]. The safety profile of mifepristone makes it well-suited for a safe metastatic chemopreventive candidate.

40)   Med Res Rev. 2014 Sep;34(5):979-1000. doi: 10.1002/med.21311. Epub 2014 Mar 1.
The unique pharmacological characteristics of mifepristone (RU486): from terminating pregnancy to preventing cancer metastasis.
Chen J1, Wang J, Shao J, Gao Y, Xu J, Yu S, Liu Z, Jia L.

Mifepristone (RU486) is a born-for-woman molecule discovered three decades ago. Unlike those antihypertensive and antipsychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential. Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing our views on the drug beyond its abortifacient scope. Here we briefly review its metabolism and pharmacokinetic properties including its unique enterohepatic circulation, its mechanisms of actions involving antiprogesterone and antiglucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, downregulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration.

We comprehensively analyze recent results from preclinical and clinical studies using mifepristone as an anticancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma. Although mifepristone has more benefits for global public health than we originally thought, its effect as a postmetastatic chemotherapeutic agent is limited. Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention.

mifepristone 200 mg daily x 2 years

41) Ji, Yongli, et al. “Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005.” Journal of Clinical Oncology 33.34 (2015): 4093-4098.
Patients were randomly assigned to either oral mifepristone 200 mg daily or placebo for 2 years (Fig 1). The dose of 200 mg was chosen for its antiprogesterone activity and its minimal antiglucocorticoid activity.22 Patients carried a warning card to alert medical personnel that the investigational treatment could cause subclinical adrenal insufficiency and to recommend administration of exogenous glucocorticoids in case of emergency.

42) Ozsvári, Béla, Rebecca Lamb, and Michael P. Lisanti. “Repurposing of FDA-approved drugs against cancer–focus on metastasis.” Aging (Albany NY) 8.4 (2016): 567.

43) Starving Cancer Cells Out of Existence. Doctors Knock Out Cancer Stem Cells With A Common Antibiotic and Finish Off Treatment-Resistant Stem Cells With Vitamin C
By Bill Sardi June 12, 2017 Lew Rockwell

Metformin

44)  Patricia Sancho, et al. “MYC/PGC-1a Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.” Cell Metabolism 22 (2015): 1-16. MYC Determines Metabolic Phenotype Pancreatic Cancer Stem Cells Metformin Patricia Sancho Cell Metabolism 2015

The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.

Atovaquone

45) Patent

Methods of treating cancer with atovaquone-related compounds WO 2015050844 A1
Described herein are, inter alia, methods for decreasing the growth of a cancer cell, the method comprising delivering to a target cancer cell a growth-inhibitory amount of an atovaquone-related compound, wherein, prior to the delivery, an increased level of activation of the mTOR pathway in the cancer compared to a control level of activation of the mTOR pathway has been found. Also provided are methods for determining the susceptibility of cancer to treatment with an atovaquone-related compound and for assessing the success of therapy with such a compound.

46)   Oncotarget. 2016 Jun 7;7(23):34084-99. doi: 10.18632/oncotarget.9122.
Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.  Fiorillo M1,2,3, Lamb R1, Tanowitz HB4, Mutti L5, Krstic-Demonacos M5, Cappello AR3, Martinez-Outschoorn UE6, Sotgia F1,2, Lisanti MP1,2.

Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/- CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone’s action on CSCs (1 μM) is >50 times less than its average serum concentration in humans.

Atovaquone can be administered alone as a liquid suspension (brand name Mepron) or in combination with Proguanil (brand name Malarone). Atovaquone is a highly lipophilic compound, with limited solubility in water. The bioavailability of atovaquone is dependent on its formulation and the diet, and its absorption is enhanced by high-fat food intake. Importantly, with current oral formulations, the average serum concentration of atovaquone in humans is > 50 μM.

Atovaquone is a quinone that functions as a competitive inhibitor of co-enzyme Q10

When atovaquone suspension was administered in humans with food at the standard regimen of 750 mg twice daily, the average steady-state plasma concentration was 21.0 ± 4.9 μg/mL, and the minimum plasma concentration was 16 ± 3.8 μg/mL [29]. It should be noted that in our experiments we have effectively ablated mammosphere formation with 10 μM atovaquone, which corresponds to 3.66 μg/mL. Thus, the clinically relevant, therapeutic plasma concentration of atovaquone is 5-times higher than the concentration that completely blocks the expansion of CSCs.

47) KAWADA, Hiroshi, et al. “Phase I Clinical Trial of Intravenous L-ascorbic Acid Following Salvage Chemotherapy for Relapsed B-cell non-Hodgkin’s Lymphoma.” The Tokai journal of experimental and clinical medicine 39.3 (2014): 111-115. Intravenous Ascorbic Acid Following Chemotherapy for Relapsed B-Cell Lymphoma KAWADA Hiroshi Tokai journal 2014

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48) Wang, S. Q., et al. “New application of an old drug: Antitumor activity and mechanisms of doxycycline in small cell lung cancer.” International journal of oncology 48.4 (2016): 1353.

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Summary
Doxycycline Vitamin C Anti Cancer Synergy
Article Name
Doxycycline Vitamin C Anti Cancer Synergy
Description
Doxycycline Vitamin C Combination Eradicates Cancer Stem Cells
Author
jeffrey dach md