Research Papers:

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

Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia and Michael P. Lisanti _

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Oncotarget. 2017; 8:67269-67286. https://doi.org/10.18632/oncotarget.18428

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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

Correspondenc to:

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.

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