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.
Highlights
We have demonstrated that cancer stem cells (CSCs) critically rely on mitochondrial biogenesis and oxidative metabolism for their propagation [1, 2]
Secondary endpoints were used to determine if pre-operative treatment with Doxycycline in the same breast cancer patients resulted in inhibition of CSC propagation and a reduction of mitochondrial markers
Doxycycline and Azithromycin display a marked increased efficacy in the inhibition of mammosphere formation, relative to when the drugs are used alone. These results suggest that a com-bination of Doxycycline and Azithromycin might have more therapeutic efficacy, than the two drugs used alone
Summary
We have demonstrated that cancer stem cells (CSCs) critically rely on mitochondrial biogenesis and oxidative metabolism for their propagation [1, 2]. Quantitatively similar results were obtained with several other human breast cancer cell lines, such as T47D [ER(+)] and MDA-MB-231 (triple-negative). The ABC trial aimed to assess the anti-proliferative and anti-CSC mechanistic actions of Doxycycline in early breast cancer patients [5]. The primary endpoint of the ABC trial was to determine whether short-term (2 weeks) pre-operative treatment with oral Doxycycline of stage I-to-III early breast cancer patients resulted in inhibition of tumor proliferation markers, as determined by a reduction in tumor Ki67 from baseline (pretreatment) to post-treatment, at the time of surgical excision [5]. Secondary endpoints were used to determine if pre-operative treatment with Doxycycline in the same breast cancer patients resulted in inhibition of CSC propagation and a reduction of mitochondrial markers
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