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Gynecol Oncol. 2019 Aug;154(2):432-440. doi: 10.1016/j.ygyno.2019.05.022. Epub 2019 Jun 6.

Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth.

Author information

1
Division of Gynecologic Oncology, NorthShore University HealthSystem, 2650 Ridge Avenue, Suite 1507, Walgreen Building, Evanston, IL 60201, USA; Section of Gynecologic Oncology, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2050, Chicago, IL 60637, USA.
2
Division of Gynecologic Oncology, NorthShore University HealthSystem, 2650 Ridge Avenue, Suite 1507, Walgreen Building, Evanston, IL 60201, USA.
3
Division of Gynecologic Oncology, NorthShore University HealthSystem, 2650 Ridge Avenue, Suite 1507, Walgreen Building, Evanston, IL 60201, USA; Section of Gynecologic Oncology, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2050, Chicago, IL 60637, USA. Electronic address: grodriguez@northshore.org.

Abstract

OBJECTIVE:

Recent data show that simvastatin (SIM) and metformin (MET) have anti-proliferative effects in endometrial cancer cells. The combination (MET+SIM) inhibits tumor growth and metastasis in prostate cancer cells which possess similar molecular alterations to many early endometrial cancers. We tested the hypothesis that the anti-proliferative effects of MET+SIM in endometrial cancer cells would be greater than the effects of each agent alone.

METHODS:

RL95-2, HEC1B, and Ishikawa endometrial cancer cell lines were treated with MET and/or SIM. Growth inhibition was measured by MTS cell proliferation assays. Apoptosis was evaluated by caspase-3, Annexin V, and TUNEL assays and by apoptosis markers (BAX, Bcl-2, Bim) using western blot. Bim was silenced using Bim siRNA to confirm this apoptotic pathway. Treatment effects on the mTOR pathway were investigated by western blot using antibodies to phosphorylated (phospho)-AMPK and phospho-S6.

RESULTS:

MET+SIM synergistically inhibited growth in all three cell lines. The combination induced apoptosis as measured by TUNEL, Annexin V, and caspase-3 assays. Bim siRNA transfection abrogated this effect-silencing Bim in MET+SIM-treated RL95-2 cells rescued cell viability in MTS assays and reduced caspase-3 activity compared with control siRNA-transfected cells. Combination treatment upregulated phosphorylated AMPK and downregulated downstream phosphorylated S6, suggesting mTOR inhibition as a mechanism for these anti-proliferative effects.

CONCLUSIONS:

MET+SIM treatment synergistically inhibits endometrial cancer cell viability. This may be mediated by apoptosis and mTOR pathway inhibition. Our results provide preclinical evidence that the combination of these well-tolerated drugs may warrant further clinical investigation for endometrial cancer treatment.

KEYWORDS:

Apoptosis; Endometrial cancer; Metformin; Statin; mTOR

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