Metformin Eliminates CD133high/CD44high Prostate Cancer Stem Cells Via Cell Cycle Arrest and Apoptosis

Abstract

Objectives: Cancer stem cells (CSCs), a small subpopulation of tumors, are responsible for chemo-radioresistance, metastasis, and cancer recurrence. The main aim of the present study is to investigate the potential effects of metformin on prostate CSCs (PCSCs). Methods: Flow cytometry was used to isolate cells with co-expression of CD133 and CD44. Sorted PCSCs were treated with different concentrations of metformin to determine the effects of metformin on cell viability using MTT assay. The association of cells exposure to metformin with apoptotic cell death and caspase activity, as well as cell cycle, were performed using the Muse Cell Analyzer. Results: In our study, for the first time we demonstrated the anti-cancer effects of metformin on PCSCs. Our results revealed that treatment with metformin reduced cell viability in CD133high/CD44high cells in a dose- and time-dependent manner. Metformin significantly induced early apoptosis and triggered the activity of several caspases associated with the apoptotic process. Metformin significantly altered the cell cycle distribution in CD133high/CD44high cells, leading to G0/G1 phase arrest. Conclusion: The results of the study revealed that metformin triggers cell death and apoptosis and modulates cell cycle distribution in CD133high/CD44high PCSCS. The present study raises the possibility that metformin is a potential anti-cancer agent for targeting PCSCs. Keywords: Prostate cancer, cancer stem cell, metformin