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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01073

Antidiabetic biguanides are potent hypoxic radiosensitizers through targeting of mitochondrial respiration and re-oxygenation of tumor cells

 Sven de Mey1, Heng Jiang1,  Cyril Corbet2, Hui Wang1,  Inès Dufait1, Ka Lun Law1,  Estelle Bastien2, Valeri Verovski1,  Thierry Gevaert1,  Olivier Feron2 and  Mark De Ridder1*
  • 1Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Belgium
  • 2Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Belgium

Background and purpose: The anti-diabetic biguanide drugs metformin and phenformin exhibit antitumor activity in various models. However, their radiomodulatory effect under hypoxic conditions, particularly for phenformin, is largely unknown. This study therefore examines whether metformin and phenformin as mitochondrial complex I blockades could overcome hypoxic radioresistance through inhibition of oxygen consumption.
Material and methods: A panel of colorectal cancer cells (HCT116, DLD-1, HT29, SW480, and CT26) was exposed to metformin or phenformin for 16 hours at indicated concentrations. Afterwards, cell viability was measured by MTT and colony formation assays. Apoptosis and reactive oxygen species were detected by flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) was examined by western blot. Mitochondria complexes activity and oxygen consumption rate were measured by seahorse analyzer. The radiosensitivity of tumor cells was assessed by colony formation assay under aerobic and hypoxic conditions. The in vitro findings were further validated in colorectal CT26 tumor model.
Results: Metformin and phenformin inhibited mitochondrial complex I activity and subsequently reduced oxygen consumption rate in a dose-dependent manner starting at 3mM and 30μM respectively. As a result, the hypoxic radioresistance of tumor cells was counteracted by metformin and phenformin with an enhancement ratio about 2 at 9mM and 100μM respectively. Regarding intrinsic radioresistance, both of them did not exhibit any effect although there was an increase of phosphorylation of AMPK and reactive oxygen species production. In tumor-bearing mice, metformin or phenformin alone did not show any anti-tumor effect. While in combination with radiation, both of them substantially delayed tumor growth and enhanced radioresponse respectively by 1.3 and 1.5 folds.
Conclusions: Our results demonstrate that metformin and phenformin overcome hypoxic radioresistance through inhibition of mitochondrial respiration, and provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.

Keywords: Hypoxic radiosensitivity, oxygen consumption rate, colorectal cancer, Radiation Oncology, Reactive Oxygen Species, Cell Hypoxia, Radiation, mitochondrial oxidative stress

Received: 15 Jun 2018; Accepted: 05 Sep 2018.

Edited by:

OLIVIER CUVILLIER, Centre national de la recherche scientifique (CNRS), France

Reviewed by:

Chris R. Triggle, Weill Cornell Medicine- Qatar, Qatar
Lucas Sullivan, Fred Hutchinson Cancer Research Center, United States  

Copyright: © 2018 de Mey, Jiang, Corbet, Wang, Dufait, Law, Bastien, Verovski, Gevaert, Feron and De Ridder. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Mark De Ridder, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium, Mark.DeRidder@uzbrussel.be