title: 1,4-Diselenophene-1,4-diketone triggers caspase-dependent apoptosis in human melanoma A375 cells through induction of mitochondrial dysfunction.
abstract: Epidemiological, preclinical and clinical studies have supported the role of selenocompounds as potential cancer chemopreventive and chemotherapeutic agents. In this study, a novel selenophene-based compound, 1,4-diselenophene-1,4-diketone (DSeD), has been synthesized by Double Friedel-Crafts reaction and identified as a potent antiproliferative agent against a panel of six human caner cell lines. Despite this potency, DSeD was relatively nontoxic toward human normal cells, HS68 fibroblasts and HK-2 kidney cells. These results suggest that DSeD possesses great selectivity between cancer and normal cells. Induction of apoptosis in human melanoma A375 cells by DSeD was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Activation of caspase-9 and depletion of mitochondrial membrane potential indicated the initiation of the mitochondria-mediated apoptosis pathway. Pretreatment of cells with general caspase inhibitor z-VAD-fmk and caspase-9 inhibitor z-LEHD-fmk significantly suppressed the cell apoptosis, demonstrating the important roles of caspase and mitochondria in DSeD-induced apoptotic cell death. Furthermore, DSeD-induced apoptosis was found independent of reactive oxygen species generation. Taken together, our results suggest that DSeD induces caspase-dependent apoptosis in A375 cells through activation of mitochondria-mediated apoptosis pathway.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, Guangdong Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Huang
authors.forename: Yum-Shing
authors.initials: YS
authors.lastname: Wong
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C573103:1,4-diselenophene-1,4-diketone; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D005609:Free Radicals; D007659:Ketones; D009842:Oligopeptides; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases