Abstract 4355: Metformin potentiates the efficacy of radiotherapy of tumors by eliminating cancer stem cells

Abstract

Abstract Metformin, a widely used drug for type II diabetes, possess significant anti-cancer property. In a recent study, metformin was able to selectively kill chemoresistant cancer stem cells (CSCs). It has been known that CSCs are resistant to irradiation and, thus, they are responsible for the recurrence of cancer after radiotherapy. The purpose of the present study was to investigate whether metformin enhances the response of tumors to radiotherapy by eradicating radioresistant CSCs. An incubation with metformin at 0.1 mM – 10 mM for 72 hours caused clonogenic cell death in a dose-dependent manner in MCF-7 human breast cancer cells, MIA PaCa-2 human pancreatic cancer cells, and FSaII mouse fibrosarcoma cells. In addition, the clonogenic cell death was enhanced by using the combination of metformin and irradiation. We then investigated the effect of metformin on CSCs of the three cell lines, which were identified by ALDH-1 activity, CD24low/CD44+ expression, and SP method. Metformin was preferentially cytotoxic to CSCs in all these cell lines. The formation of mammospheres from MCF-7 cells was also markedly inhibited by metformin. Both metformin and irradiation activated AMPK and suppressed the mTOR-S6K signaling pathway. Combined treatment of cells with metformin and irradiation was far more effective in activating AMPK and suppressing the mTOR-S6K pathway. The combined effects of metformin and X-irradiation on the growth of FSaII tumors induced in the hind legs of C3H mice were studied. Metformin treatment at 50 – 100 mg/kg/day, i.p., slightly suppressed the tumor growth, but it strikely potentiated the response of tumors to 20 Gy X-irradiation in a single exposure. It was likely that metformin treatment depleted the radioresistant CSCs in the tumors, thereby markedly enhancing the response of tumors to irradiation. However, in addition to killing CSCs, the possibility that metformin radiosensitized CSCs as well as non-CSCs could not be excluded. Our results demonstrated for the first time that metformin is potentially useful for enhancing the efficacy of radiotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2011-4355