Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth
| Autor: | Josephine S. Kim, Gustavo C. Rodriguez, Larry G. Thaete, Jane Turbov, R. Rosales |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Simvastatin Blotting Western Apoptosis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Annexin Cell Line Tumor medicine Humans Viability assay PI3K/AKT/mTOR pathway Cell growth business.industry Caspase 3 Endometrial cancer TOR Serine-Threonine Kinases Obstetrics and Gynecology Transfection medicine.disease Metformin Endometrial Neoplasms Gene Expression Regulation Neoplastic 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research Drug Therapy Combination Female Growth inhibition business |
| Zdroj: | Gynecologic oncology. 154(2) |
| ISSN: | 1095-6859 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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