title: Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells.
abstract: Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration‑dependent cytotoxicity in 4 TCC cell lines (IC50s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27kip1, suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer.
authors.affiliation: Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, R.O.C.
authors.forename: Yen Ta
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.
authors.forename: Chuan Chu
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, R.O.C.
authors.forename: Tzu Chun
authors.initials: TC
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Tzu Chi University, Hualien, Taiwan, R.O.C.
authors.forename: Ted H
authors.initials: TH
authors.lastname: Chiu
authors.affiliation: Department of Medicine, Tzu Chi University, Hualien, Taiwan, R.O.C.
authors.forename: Pei Chun
authors.initials: PC
authors.lastname: Lai
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D053938:DNA Fragmentation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009285:Naphthoquinones / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D064249:Securin / Q000096:biosynthesis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000187:drug effects / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D064249:Securin; D000077022:Survivin; D003841:Deoxycytidine; D050760:Cyclin-Dependent Kinase Inhibitor p27; C025946:3-methyladenine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; C523798:sepantronium; D020123:Sirolimus; D000093542:Gemcitabine