期刊
ONCOTARGET
卷 6, 期 27, 页码 23548-23560出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4556
关键词
ovarian cancer; metformin; hyperglycemia; glycolysis; c-Myc
资金
- National Institutes of Health
- University of Chicago Cancer Center Support Grant [CA014599]
- Mayo Clinic SPORE in Ovarian Cancer [P50CA136393]
- National Cancer Institute [5R01CA111882-07, 1R01CA169604-01A1]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [2K12HD000849-26]
- American Board of Obstetrics and Gynecology
- Illinois Department of Public Health Penny Severns Research Fund
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.
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