title: Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species.
abstract: Postoperative chemotherapy for Colorectal cancer (CRC) patients is not all effective and the main reason might lie in cancer stem cells (CSCs). Emerging studies showed that CSCs overexpress some drug-resistance related proteins, which efficiently transport the chemotherapeutics out of cancer cells. Salinomycin, which considered as a novel and an effective anticancer drug, is found to have the ability to kill both CSCs and therapy-resistant cancer cells. To explore the potential mechanisms that salinomycin could specifically target on therapy-resistant cancer cells in colorectal cancers, we firstly obtained cisplatin-resistant (Cisp-resistant) SW620 cells by repeated exposure to 5 μmol/l of cisplatin from an original colorectal cancer cell line. These Cisp-resistant SW620 cells, which maintained a relative quiescent state (G0/G1 arrest) and displayed stem-like signatures (up-regulations of Sox2, Oct4, Nanog, Klf4, Hes1, CD24, CD26, CD44, CD133, CD166, Lgr5, ALDH1A1 and ALDH1A3 mRNA expressions) (p < 0.05), were sensitive to salinomycin (p < 0.05). Salinomycin did not show the influence on the cell cycle of Cisp-resistant SW620 cells (p > 0.05), but could induce cell death process (p < 0.05), with increased levels of LDH release and MDA contents as well as down-regulations of SOD and GSH-PX activities (p < 0.05). Our data also showed that the pro-apoptotic genes (Caspase-3, Caspase-8, Caspase-9 and Bax) were up-regulated and the anti-apoptotic gene Bcl-2 were down-regulated in Cisp-resistant SW620 cells (p < 0.05). Accumulated reactive oxygen species and dysregulation of some apoptosis-related genes might ultimately lead to apoptosis in Cisp-resistant SW620 cells. These findings will provide new clues for novel and selective chemotherapy on cisplatin-resistant colorectal cancer cells.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xue
authors.forename: Songbing
authors.initials: S
authors.lastname: He
authors.forename: Yuting
authors.initials: Y
authors.lastname: Kuang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Shaoji
authors.initials: S
authors.lastname: Chen
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Zhi
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Guo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D000090062:Kruppel-Like Factor 4; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D020169:Caspases; D002945:Cisplatin; D000090062:Kruppel-Like Factor 4; D010088:Oxidoreductases; D019253:Proto-Oncogene Proteins c-bcl-2; D011714:Pyrans; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C000715467:KLF4 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Apoptosis; Cisplatin-resistant; Reactive oxygen species; Salinomycin