Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization |
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Authors: | Kim Kwang-Youn Yu Sun-Nyoung Lee Sun-Yi Chun Sung-Sik Choi Yong-Lark Park Yeong-Min Song Chung Seog Chatterjee Bandana Ahn Soon-Cheol |
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Institution: | aDepartment of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea;bCitrus Research Station, National Institute of Horticultural & Herbal Science, RDA, Jeju 699-946, Republic of Korea;cDepartment of Food Science, International University of Korea, Jinju 660-759, Republic of Korea;dDepartment of Biotechnology, Faculty of Natural Resources and Life Science Dong-A University, Busan 604-714, Republic of Korea;eDepartment of Molecular Medicine & Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA;fMedical Research Institute, Pusan National University, Yangsan 626-870, Republic of Korea |
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Abstract: | The anticancer activity of salinomycin has evoked excitement due to its recent identification as a selective inhibitor of breast cancer stem cells (CSCs) and its ability to reduce tumor growth and metastasis in vivo. In prostate cancer, similar to other cancer types, CSCs and/or progenitor cancer cells are believed to drive tumor recurrence and tumor growth. Thus salinomycin can potentially interfere with the end-stage progression of hormone-indifferent and chemotherapy-resistant prostate cancer. Androgen-responsive (LNCaP) and androgen-refractive (PC-3, DU-145) human prostate cancer cells showed dose- and time-dependent reduced viability upon salinomycin treatment; non-malignant RWPE-1 prostate cells were relatively less sensitive to drug-induced lethality. Salinomycin triggered apoptosis of PC-3 cells by elevating the intracellular ROS level, which was accompanied by decreased mitochondrial membrane potential, translocation of Bax protein to mitochondria, cytochrome c release to the cytoplasm, activation of the caspase-3 and cleavage of PARP-1, a caspase-3 substrate. Expression of the survival protein Bcl-2 declined. Pretreatment of PC-3 cells with the antioxidant N-acetylcysteine prevented escalation of oxidative stress, dissipation of the membrane polarity of mitochondria and changes in downstream molecular events. These results are the first to link elevated oxidative stress and mitochondrial membrane depolarization to salinomycin-mediated apoptosis of prostate cancer cells. |
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Keywords: | Abbreviations: CSC cancer stem cell MMP mitochondrial membrane potential ROS reactive oxygen species MTT 3-(4 5-dimethyl-thiazol-2-yl)-2 5-diphenyl-tetrazolium bromide NAC N-acetylcysteine DAPI 4&prime 6-diamidino-2-phenylindole dihydrochloride DiOC6 3 3-dihexyloxacarbocyanine DCFH-DA 2&prime -7&prime -dichlorodihydrofluorescein diacetate PARP-1 poly (ADP-ribose) polymerase-1 FITC fluorescein isothiocyanate PI propidium iodide |
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