Source Article in Science Daily Cancer stem cells, which fuel the growth of new and existing tumors, can be eliminated by a treatment combination of first antibiotics followed by high-dose vitamin C intravenously. So say researchers at the University of Salford, following results from their experimental study.The antibiotic, Doxycycline, followed by single doses of ascorbic acid (vitamin C), was surprisingly effective at killing cancer stem cells in an experimental study. Or as the researchers say, "in boxing terms, this would be similar to a combination of two blows delivered in quick succession; a punch from the left hand followed by a knockout with the right."-----------------------------------------
Credit where credit is due.
Dr. Albert M. Kroon | physician-biochemist | former Professor of Physiological Chemistry RUGHAARLEM - Haarlemmer Albert Kroon is firmly convinced he is right and dreams of a good and cheap cancer drug. Known among medics as an antibiotic for Lyme disease, but according to him a good working cure for cancer.Dr. Albert M. Kroon (1934) studied medicine and biochemistry at UVA. There he was attached to the Laboratory of Physiological Chemistry under Professor E.C. Slater, his supervisor in 1066, from 1961 to 1969. In 1969 he was appointed to the RUG, first as lecturer, later as professor of Physiological Chemistry. There he started experimental oncological research with his group. In 1962, he established that isolated mitochondria, the electricity houses of the cell, are capable of DNA-dependent protein synthesis. It appeared that this action could be inhibited by existing antibiotics. He saw in this an opportunity to use antibiotics to fight cancer. In cell cultures and animal models, this is indeed possible. Doxycycline, a widely prescribed drug, is well suited for this purpose, Retrospective clinical findings appeared to support the premise. In 1991, he shifted his work to allergy. Unfortunately, due to circumstances, the research was not followed up then. Since 2011, he has been studying this issue again. He is a visiting scientist at UCL in London.-----------------------------------------The researchers say their method offers a new treatment option to prevent cancer cells from becoming resistant to certain cancer treatments (chemo) and how combinations of treatments can be developed to overcome resistance to certain drugs (chemo).Professor Michael Lisanti, who designed the study, explains: "We now know that some of the cancer cells escape chemotherapy and develop drug resistance, we set up these new treatment combinations to find out how they do it.In their study report, their approach is illustrated in many graphs, but is not of interest to laymen. Here, however, is the strategy the researchers used. First weaken and starve the cancer stem cells with doxycycline and then deliver the killing blow with vitamin C:Figure 12: Vitamin C and Doxycycline: A synthetic lethal combination therapy for eradicating CSCs. Note that both OXPHOS and the glycolytic pathway jointly contribute to ATP production. Doxycycline inhibits mitochondrial biogenesis and OXPHOS, by acting viamitochondrial ribosomal proteins (MRPs); Vitamin C inhibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH. Therefore, their use together, as a sequential drug combination, will more severely target cell metabolism and energy production, thereby preventing or blocking the propagation of CSCs. The researchers at Salford tried the combinations below but always using doxycycline first to weaken/ starve the cancer stem cells:
Figure 9: Metabolic inhibitors successfully employed for the eradication of DoxyR CSCs. Briefly, a list of small molecules that we successfully used in conjunction with Doxycycline is shown. These include 9 known inhibitors of OXPHOS, glycolysis and autophagy. Two natural products (Vitamin C and Berberine), six clinically-approved drugs (Atovaquone, Chloroquine, Irinotecan, Sorafenib, Niclosamide, and Stiripentol) and one experimental drug (2-DG), are all highlighted.
"We suspected that the answer lies in the fact that certain cancer cells - which we call metabolically flexible - are able to change fuel sources, so when chemo treatment reduces the availability of a particular nutrient, the flexible cancer cells can feed themselves with an alternative energy source." said Professor Michael Lisanti
This new combination treatment prevents cancer cells from changing their diet (metabolic inflexibility) and will effectively starve the cancer stem cells by preventing them from using other available types of biofuels.The researchers at the University of Salford's Biomedical Research Center added Doxycycline in increasing doses over a three-month period to create metabolic inflexibility. The goal was to leave the cancer cells alive, but try to weaken and deplete them so that they would be much more vulnerable to starvation, by a second so-called metabolic "punch".First, the researchers inhibited the mitochondria in the tumor cell, feeding the cancer cells only with glucose as a fuel source; then they took away their glucose and effectively killed the cancer cells with vitamin C.
Figure 10: Glycolysis inhibitors reduce mammosphere formation in MCF7 DoxyR cells. Evaluation of mammosphere formation in MCF7 and MCF7 DoxyR cells cultured in low attachment plates and treated with Vehicle or increasing concentrations of the glycoysis inhibitor 2-deoxy-glucose (2 DG) (10 mM to 20 mM) for 5 days before counting A. Mammosphere formation is inhibited in MCF7 DoxyR cells cultured in low attachment plates and treated with increasing concentrations of the glycoysis inhibitor Ascorbic Acid (100 µM to 500 µM) for 5 days before counting B. Data shown are the mean ± SEM of 3 independent experiments performed in triplicate. (***) p < 0.001.
"In this scenario, vitamin C behaves as an inhibitor of glycolysis, which fuels energy production in the mitochondria, the" powerhouse "of the cell," explains co-author Dr. Federica Sotgia. The Salford team recently showed that vitamin C is up to 10 times more effective in stopping cancer cell growth than pharmaceuticals such as 2-DG, but they say that when vitamin C is combined with an antibiotic, it becomes up to 10 times more effective, making it nearly 100 times more effective than 2-DG. Since Doxycycline and vitamin C are both nontoxic, this can dramatically reduce the potential side effects of anticancer therapy (chemo). The Salford team also examined eight other drugs that could be used as a "second hit" after antibiotic use, including berberine (a natural product) - and a number of inexpensive nontoxic FDA-approved drugs.Professor Lisanti added: "This is further evidence that vitamin C and other non-toxic agents can play a role in the fight against cancer. "Our results indicate that it is a promising agent for clinical trials and an adjunct to more conventional therapies to prevent tumor recurrence, further disease progression and metastasis." It is an interesting study and the full study report: Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)with detailed explanation of how they went about it is available for free viewing. Here is the abstract with extensive original conclusion
Vitamin C and antibiotics: A new one-two 'punch' for knocking-out cancer stem cells.
Journal Reference:
- 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
Oncotarget. 2017; 8:67269-67286. https://doi.org/10.18632/oncotarget.18428
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Ernestina Marianna De Francesco1,2, Gloria Bonuccelli3, Marcello Maggiolini1, Federica Sotgia3 and Michael P. Lisanti3
1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
2 The Paterson Institute, University of Manchester, Withington, United Kingdom
3 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester, United Kingdom
