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 ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382 2017, 'Vitamin C and Doxycycline : a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)' , Oncotarget, 2017 (8) , pp. 67269-67286.

Preview	PDF - Published Version Available under License Creative Commons Attribution. Download (4MB) | Preview
	PDF - Accepted Version Restricted to Repository staff only Download (2MB) | Request a copy

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:	Publication
Depositing User:	F Sotgia
Date Deposited:	12 Jul 2017 10:44
Last Modified:	15 Feb 2022 22:12
URI:	https://usir.salford.ac.uk/id/eprint/42937

Actions (login required)

Edit record (repository staff only)