Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams

// Eun Ho Kim 1 , Mi-Sook Kim 2 , Yoshiya Furusawa 3 , Akiko Uzawa 3 , Soorim Han 1 , Won-Gyun Jung 1 , Sei Sai 3 1 Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Gongneung-dong, Nowon-Gu, Seoul, South Korea 2 Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea 3 Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan Correspondence to: Mi-Sook Kim, email: mskim@kirams.re.kr Sei Sai, email: sai.sei@qst.go.jp Keywords: metformin, carbon ion beam, radiosensitivity, hepatocellular carcinoma cell, DNA damage Received: August 04, 2016 Accepted: October 19, 2016 Published: October 27, 2016 ABSTRACT The purpose of this study was to investigate the effect of metformin on the responses of hepatocellular carcinoma (HCC) cells to γ–rays (low-linear energy transfer (LET) radiation) and carbon-ion beams (high-LET radiation). HCC cells were pretreated with metformin and exposed to a single dose of γ–rays or carbon ion beams. Metformin treatment increased radiation-induced clonogenic cell death, DNA damage, and apoptosis. Carbon ion beams combined with metformin were more effective than carbon ion beams or γ-rays alone at inducing subG1 and decreasing G2/M arrest, reducing the expression of vimentin, enhancing phospho-AMPK expression, and suppressing phospho-mTOR and phospho-Akt. Thus, metformin effectively enhanced the therapeutic effect of radiation with a wide range of LET, in particular carbon ion beams and it may be useful for increasing the clinical efficacy of carbon ion beams.