Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial
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Published on: June 20, 2015
Akira Mitsuhashi1, Takako Kiyokawa, Yasunori Sato
1Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Background:
Metformin, an antidiabetic drug, decreases the incidence of various cancers in diabetic patients. Metformin-induced inhibition of cancer cell proliferation has been confirmed in vitro but not in humans. Because endometrial cancer is associated with insulin resistance, the authors investigated whether a diabetes-therapeutic metformin dose inhibits cancer cell growth in patients with endometrial cancer.
Methods:
A dose of metaformin was administered (1500-2250 mg/day) to 31 patients with endometrial cancer preoperatively for 4 to 6 weeks. Cell proliferation was assessed in patient tissues using immunohistochemical and Western blot analyses and DNA synthesis was measured in serum using a thymidine uptake assay. All statistical tests were 2-sided. P values of < .05 were considered statistically significant.
Results:
Preoperative metformin treatment decreased DNA synthesis in sera and significantly reduced the Ki-67 (mean proportional decrease, 44.2%; 95% confidence interval [95% CI], 35.4-53.0 [P < .001]) and topoisomerase IIα (mean proportional decrease, 36.4%; 95% CI, 26.7-46.0 [P < .001]) labeling indices. Levels of phospho-ribosomal protein S6 and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were found to be significantly decreased and phospho-adenosine monophosphate-activated protein kinase and p27 levels were significantly increased. Preoperative metformin use caused significant decreases in circulating factors, including insulin, glucose, insulin-like growth factor 1, and leptin. DNA synthesis-stimulating activity in patient sera was significantly decreased during metformin administration.
Conclusions:
An antidiabetic dose of metformin inhibited endometrial cancer cell growth in vivo, an effect likely due to its effect on humoral factor(s). This translational study provides considerable rationale to initiate large clinical trials.
Insights
Metformin, an antidiabetic drug, was found to inhibit endometrial cancer cell growth in patients. This study suggests metformin
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Metformin, an antidiabetic medication, shows potential in reducing cancer incidence in diabetic patients.
- In vitro studies confirm metformin's ability to inhibit cancer cell proliferation, but human data is limited.
- Endometrial cancer is linked to insulin resistance, prompting investigation into metformin's effects.
Purpose of the Study:
- To investigate if a diabetes-therapeutic dose of metformin inhibits cancer cell growth in patients with endometrial cancer.
- To assess the impact of metformin on cell proliferation markers and humoral factors in endometrial cancer patients.
Main Methods:
- 31 endometrial cancer patients received metformin (1500-2250 mg/day) preoperatively for 4-6 weeks.
- Cell proliferation was assessed via immunohistochemistry and Western blot.
- Serum DNA synthesis was measured using a thymidine uptake assay.
Main Results:
- Metformin significantly reduced DNA synthesis, Ki-67, and topoisomerase IIα labeling indices.
- Key signaling pathway markers (phospho-S6, phospho-ERK1/2) decreased, while others (phospho-AMPK, p27) increased.
- Metformin decreased circulating insulin, glucose, IGF-1, and leptin levels, reducing serum DNA synthesis-stimulating activity.
Conclusions:
- An antidiabetic dose of metformin effectively inhibited endometrial cancer cell growth in vivo.
- The observed effect is likely mediated by metformin's influence on humoral factors.
- Results provide a strong rationale for large clinical trials of metformin in endometrial cancer.
