Vitamin C and Doxycycline : A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)

De Francesco, EM, Bonuccelli, G, Maggiolini, M, Sotgia, F and Lisanti, MP 2017, 'Vitamin C and Doxycycline : A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)' , Oncotarget .

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Abstract

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.

Item Type: Article
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Oncotarget
Publisher: Impact Journals
ISSN: 1949-2553
Related URLs:
Depositing User: F Sotgia
Date Deposited: 12 Jul 2017 10:44
Last Modified: 23 Oct 2017 13:16
URI: http://usir.salford.ac.uk/id/eprint/42937

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