title: Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined.
abstract: Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.
authors: Department of Microbiology, College of Medicine, Inha University, Incheon, Korea.
authors: Hyemi
authors: H
authors: Lee
authors: Department of Microbiology, College of Medicine, Inha University, Incheon, Korea.
authors: Heon Joo
authors: HJ
authors: Park
authors: Department of Pharmacology, College of Medicine, Inha University, Incheon, Korea.
authors: Chang-Shin
authors: CS
authors: Park
authors: Department of Microbiology, College of Medicine, Inha University, Incheon, Korea.
authors: Eun-Taex
authors: ET
authors: Oh
authors: Department of Microbiology, College of Medicine, Inha University, Incheon, Korea.
authors: Bo-Hwa
authors: BH
authors: Choi
authors: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors: Brent
authors: B
authors: Williams
authors: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors: Chung K
authors: CK
authors: Lee
authors: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors: Chang W
authors: CW
authors: Song
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D008687:Metformin