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.  Safety studies on lymphoma patients receiving 75 grams of vitamin C Intravenously had no adverse effects.  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, 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.

Cancer Stem Cells

Cancer stem cells are the reason why chemotherapy fails for rapidly proliferating cancers.   A temporary remission, or reduction in tumor size can be achieved followed by cancer relapse within months.

Conclusion: This Doxycycline/ Vitamin C combination is a dramatic breakthrough in finding an effective targeted cancer stem cell eradication strategy.  My hat comes off in admiration and thanks to Michael Lisanti and his group.

Articles with related interest:

My previous report covered Intravenous high dose Vitamin C as effective cancer chemotherapy.  My previous report covered use of common antibiotics to target cancer stem cells.

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

References

1) http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=18428&path%5B%5D=59195
Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia, Michael P. Lisanti. Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget, 2015; DOI: 10.18632/oncotarget.18428

2) http://www.medicalnewstoday.com/articles/317902.php
Combining vitamin C with antibiotics destroys cancer stem cells
By Honor Whiteman  published Tuesday 13 June 2017 670

3) http://www.worldhealth.net/news/antibiotics-and-vitamin-c-cancer-stem-cells/
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) http://www.nhs.uk/news/2017/06June/Pages/Antibiotics-and-vitamin-C-could-kill-cancer-cells.aspx
Antibiotics and vitamin C could kill cancer cells

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5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558116/
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

http://pubmedcentralcanada.ca/pmcc/articles/PMC4637276/
Barbie, David A., and Brian K. Kennedy. “Doxycycline: new tricks for an old drug.” Oncotarget 6.23 (2015): 19336.

also images
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580062/
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.

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

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.

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.

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.

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

breast CAncer

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.

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.

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.

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.

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.

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

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.

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.

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.

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

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.

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

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.

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

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

73) 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

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
74) 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

75) 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

76) 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

77) 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
78) 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.
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.
Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Abramson DH1, Rollins I, Coleman M.

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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http://cancerres.aacrjournals.org/content/75/21/4446.full
Chatzispyrou, Iliana A., et al.
“Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research.” Cancer research 75.21 (2015): 4446-4449.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565776/
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.

Lamb, Rebecca, et al. “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.” Oncotarget 6.7 (2015): 4569-4584.

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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