title: Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway.
abstract: Pancreatic cancer is relatively radioresistant, however, radiotherapy has been shown to provide efficacy in the treatment of local disease. To increase the effectiveness of radiotherapy in pancreatic cancer, radiosensitizing drugs are under development. In this study, we investigated the radiosensitizing activity of the anti-diabetic drug metformin on pancreatic cancer cells in vitro. We demonstrated that metformin radiosensitized MiaPaCa-2 and Panc1 cells with radiation enhancement ratios (ER) ranging from 1.33-1.45 with metformin concentrations of 30-100 μM, and in addition, we showed that metformin sensitized cells to gemcitabine alone or in combination with radiation treatment. In addition, we found that pancreatic cancer stem cell-like cells showed enhanced radiosensitization in a tumorsphere assay with a REF of 1.66. At these radiosensitizing doses, metformin alone had low toxicity (as shown by >75% clonogenic survival) and did not affect cell cycle. The combination of metformin and radiation yielded greater numbers of γ-H2AX foci after 1 h compared to radiation alone, suggesting increased DNA damage signaling. Examination of the AMPK pathway showed that pharmacological inhibition of AMPK signaling or RNAi of AMPKα1 reversed metformin-mediated radiosensitization. These studies show that metformin radiosensitization of pancreatic cancer cells at micromolar concentration acts through AMPK and may affect DNA damage signaling. The data indicate that metformin may increase the efficacy of radiation therapy for pancreatic cancer.
authors.affiliation: a  Department of Radiation Oncology and.
authors.forename: Aisha
authors.initials: A
authors.lastname: Fasih
authors.forename: Hosam A
authors.initials: HA
authors.lastname: Elbaz
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.forename: Andre A
authors.initials: AA
authors.lastname: Konski
authors.forename: Steven P
authors.initials: SP
authors.lastname: Zielske
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*
chemical_list: D011838:Radiation-Sensitizing Agents; D008687:Metformin; D055372:AMP-Activated Protein Kinases