期刊
ONCOTARGET
卷 8, 期 40, 页码 67269-67286出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18428
关键词
cancer stem-like cells (CSCs); doxycycline; vitamin C; mitochondrial biogenesis; mitochondrial DNA (mt-DNA)
资金
- University of Manchester
- Associazione Italiana per la Ricerca sul Cancro (AIRC) - European Union
- Healthy Life Foundation (HLF)
- University of Salford
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 16719]
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics. Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs. This type of metabolic Achilles' heel will allow us and others to more effectively starve the CSC population.
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