title: Survivin selective inhibitor YM155 promotes cisplatin‑induced apoptosis in embryonal rhabdomyosarcoma.
abstract: Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.
authors.affiliation: Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Uehara
authors.affiliation: Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Nakahata
authors.affiliation: Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Okuyama
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D002945:Cisplatin; C523798:sepantronium