Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)
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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
Michael P. Lisanti, email:
Federica Sotgia, email:
Keywords: cancer stem-like cells (CSCs), Doxycycline, Vitamin C, mitochondrial biogenesis, mitochondrial DNA (mt-DNA)
Received: May 05, 2017 Accepted: May 17, 2017 Published: June 09, 2017
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 (Hit-2: 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.
Ernestina Marianna De Francesco
Michael P. Lisanti
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