Dr. Weeks’ Comment: Finally targeting the really lethal cancer cell. “…a combination of Doxycycline (1 μM), Azithromycin (1 μM) plus Vitamin C (250 μM) very potently inhibited CSC propagation by >90%,…” This article is worth reading in its entireity

Aging (Albany NY). 2019 Apr 30; 11(8): 2202–2216.Published online 2019 Apr 19. doi: 10.18632/aging.101905PMCID: PMC6520007PMID: 31002656

Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs)

Marco Fiorillo et al

Abstract

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….

…Aging: Improving health-span and life-span

We believe that the DAV triple combination therapy that we describe here may also have implications for improving health-span and life-span, as aging is one of the most significant risk factors for the development of many human cancer types [19,20]. Moreover, we have previously demonstrated that Azithromycin, by itself, is an FDA-approved drug, with remarkable senolytic activity, that targets and removes senescent fibroblasts, such as myo-fibrobasts, with great efficiency approaching nearly 97% [21]. The accumulation of pro-inflammatory senescent cells is thought to be the primary cause of many aging-associated diseases, such as heart disease, diabetes, dementia and cancer, to name only a few [21]. Since cancer-associated fibroblasts (CAFs) are senescent myo-fibroblasts, with tumor promoting activity, this triple combination approach with Azithromycin may also effectively target the glycolytic tumor stroma of aggressive and metastatic cancers, especially those bearing the metabolic hallmarks of the “Reverse Warburg Effect” [22–28].Go to:

CONCLUSIONS

In conclusion, Phase II clinical trials will be necessary to validate the potential therapeutic efficacy of the DAV triple combination, for eradicating CSCs, in breast cancer patients.