title: Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization.
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.
authors.affiliation: Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea.
authors.forename: Kwang-Youn
authors.initials: KY
authors.lastname: Kim
authors.forename: Sun-Nyoung
authors.initials: SN
authors.lastname: Yu
authors.forename: Sun-Yi
authors.initials: SY
authors.lastname: Lee
authors.forename: Sung-Sik
authors.initials: SS
authors.lastname: Chun
authors.forename: Yong-Lark
authors.initials: YL
authors.lastname: Choi
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Chung Seog
authors.initials: CS
authors.lastname: Song
authors.forename: Bandana
authors.initials: B
authors.lastname: Chatterjee
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Ahn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D045304:Cytochromes c; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019253:Proto-Oncogene Proteins c-bcl-2; D011714:Pyrans; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C010327:salinomycin; D000095662:Polyether Polyketides; C499320:PARP1 protein, human