Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

Sci Rep. 2012;2:362. doi: 10.1038/srep00362. Epub 2012 Apr 12.

Abstract

The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, and significantly enhanced the radiation-induced growth delay of FSaII tumors (s.c.) in the legs of C3H mice. Both metformin and ionizing radiation activated AMPK leading to inactivation of mTOR and suppression of its downstream effectors such as S6K1 and 4EBP1, a crucial signaling pathway for proliferation and survival of cancer cells, in vitro as well as in the in vivo tumors.

Conclusion: Metformin kills and radiosensitizes cancer cells and eradicates radioresistant cancer stem cells by activating AMPK and suppressing mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Humans
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C3H
  • Neoplasms / enzymology
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / metabolism
  • Radiation-Sensitizing Agents / pharmacology*
  • Ribosomal Protein S6 Kinases / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Radiation-Sensitizing Agents
  • Metformin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Adenylate Kinase