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Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer.

Abstract
Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.
AuthorsLacey M Litchfield, Abir Mukherjee, Mark A Eckert, Alyssa Johnson, Kathryn A Mills, Shawn Pan, Viji Shridhar, Ernst Lengyel, Iris L Romero
JournalOncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 23548-60 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
PMID26172303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • Hypoglycemic Agents
  • Proto-Oncogene Proteins c-myc
  • Lactic Acid
  • Metformin
  • Phenformin
  • Glucose
Topics
  • Animals
  • Antineoplastic Agents (chemistry)
  • Ascites (metabolism)
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Glucose (metabolism)
  • Glycolysis
  • Humans
  • Hyperglycemia (metabolism)
  • Hypoglycemic Agents (chemistry)
  • Lactic Acid (chemistry)
  • MAP Kinase Signaling System
  • Metformin (chemistry)
  • Mice
  • Mice, Inbred C57BL
  • Ovarian Neoplasms (drug therapy, genetics, metabolism)
  • Pentose Phosphate Pathway
  • Phenformin (chemistry)
  • Proto-Oncogene Proteins c-myc (metabolism)

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