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; Lisanti, MP

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.

Citation

De Francesco, E., Bonuccelli, G., Maggiolini, M., Sotgia, F., & Lisanti, M. (2017). Vitamin C and Doxycycline : a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget, 2017(8), 67269-67286. https://doi.org/10.18632/oncotarget.18428

• Journal Article Type: Article
• Acceptance Date: May 17, 2017
• Online Publication Date: Jun 9, 2017
• Publication Date: Jun 9, 2017
• Deposit Date: Jul 12, 2017
• Publicly Available Date: Jul 12, 2017
• Journal: Oncotarget
• Publisher: Impact Journals
• Volume: 2017
• Issue: 8
• Pages: 67269-67286
• DOI: https://doi.org/10.18632/oncotarget.18428
• Publisher URL: http://dx.doi.org/10.18632/oncotarget.18428
• Related Public URLs: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=index