Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs)
Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs) https://www.ncbi.nlm.nih.gov/pubmed/31002656
Here, we devised a new strategy for eradicating cancer stem cells (CSCs), via a "synthetic-metabolic" approach, involving two FDA-approved antibiotics and a dietary vitamin supplement. This approach was designed to induce a "rho-zero-like" phenotype in cancer cells. This strategy effectively results in the synergistic eradication of CSCs, using vanishingly small quantities of two antibiotics. The 2 metabolic targets are i) the large mitochondrial ribosome and ii) the small mitochondrial ribosome. Azithromycin inhibits the large mitochondrial ribosome as an off-target side-effect. In addition, Doxycycline inhibits the small mitochondrial ribosome as an off-target side-effect. Vitamin C acts as a mild pro-oxidant, which can produce free radicals and, as a consequence, induces mitochondrial biogenesis. Remarkably, treatment with a combination of Doxycycline (1 μM), Azithromycin (1 μM) plus Vitamin C (250 μM) very potently inhibited CSC propagation by >90%, using the MCF7 ER(+) breast cancer cell line as a model system. The strong inhibitory effects of this DAV triple combination therapy on mitochondrial oxygen consumption and ATP production were directly validated using metabolic flux analysis. Therefore, the induction of mitochondrial biogenesis due to mild oxidative stress, coupled with inhibition of mitochondrial protein translation, may be a new promising therapeutic anti-cancer strategy. Consistent with these assertions, Vitamin C is known to be highly concentrated within mitochondria, by a specific transporter, namely SVCT2, in a sodium-coupled manner. Also, the concentrations of antibiotics used here represent sub-antimicrobial levels of Doxycycline and Azithromycin, thereby avoiding the potential problems associated with antibiotic resistance. Finally, we also discuss possible implications for improving health-span and life-span, as Azithromycin is an anti-aging drug that behaves as a senolytic, which selectively kills and removes senescent fibroblasts.
This research is promising, but there are some issues:
- they only test on the MCF-7 line (only one, when so many are possible), and in vitro (no mouse model), which line is ER+, and there are other good treatment options;
- they should have tested the combination as a chemosensitizer, in combination with chemo targeting ER+ breast cancer, but they didn't;
- while 1 uM DOX and 1 uM AZT are very easy to achieve and maintain for a long time in human patients, 250 uM Vitamin C can only be achieved intravenously (oral below 100 uM);
- previous exposure to each of the 3, DOX, AZT, and vitamin C significantly reduces the efficacy;
- they mention AZT as a senolytic, but "forget" to mention the 100 uM required, which is impossible to maintain in humans;
- they don't show any reduction in cancer cells numbers, only a reduction in MFE (mammosphere formation);
- it would have been interesting so see a comparison of Metformin, which dose dependently inhibits mitochondrial function, with the DOX + AZT combination, but they did no such comparison;
D, this is exciting!
The vitamin C - doxycycline combo has been out there for quite some time now. Here they are taking it another step forward. I wonder what might happen if they could take it one more step forward. For example, what might happen if they were to lead in with the doxy, arizothro, low dose vitamin C for a while and they bump it up to high dose vitamin C? Perhaps doing this would fully ATP deplete the cancer cells.
I think this is promising actually:
- although here they tested on MCF-7 line similar metabolic approach has been shown to be effective in most cancer types - also in humans not only lab - one such example is COC protocol including Doxy
- good point that with normal Vit C given orally the 250uM level cannot be achieved. But one option is to use liposomal Vit C which will help achive that level https://isom.ca/article/ascorbic-acid-dehydroascorbic-acid-concentrations-plasma-peripheral-blood-mononuclear-cells-oral-liposomal-encapsulated-intravenous-ascorbic-acid-delivery/ or we can use lower dose intravenout Vit C since the intravenous route leads to much higher levels https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260161/ or we can think of other substances to address similar mechanism.
- its no problem with the previous exposure - note that cancer cell stem populations are generated constantly, so you can at least address the fresh ones that never saw e.g. Doxy treatment that a patient may have had in the months or years before applying this approach
- indeed it would have been interesting to see the results with Metformin and also with adding 2DG