Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer

// Kyung-Min Lee 1, 2 , Minju Lee 2 , Jiwoo Lee 1, 2 , Sung Wuk Kim 4 , Hyeong-Gon Moon 2, 3 , Dong-Young Noh 2, 3 , Wonshik Han 2, 3 1 Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea 2 Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea 3 Department of Surgery, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea 4 Hanall Biopharma Co., Ltd., Seoul 138-922, Republic of Korea Correspondence to: Wonshik Han, e-mail: hanw@snu.ac.kr Keywords: metformin analog, breast cancer, stem cell population, G2/M arrest, anti-cancer drug Received: September 06, 2015 Accepted: May 05, 2016 Published: May 20, 2016 ABSTRACT Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44 + CD24 -/low populations in vitro and in vivo , indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.