title: A potent chemotherapeutic strategy for bladder cancer: (S)-methoxy-trityl-L-cystein, a novel Eg5 inhibitor.
abstract: OBJECTIVE
  Eg5, which has an essential role in the formation and maintenance of a bipolar mitotic spindle, was recently identified as an attractive target in cancer chemotherapy. We examined the anticancer activity of a novel Eg5 inhibitor for bladder cancer with particular reference to metastatic disease.
  
  
  METHODS
  We examined bladder cancer cell lines and clinical tissue samples for Eg5 expression and analyzed the antiproliferative activity of 5 Eg5 inhibitors in cell lines by cell viability assay. The anticancer efficacy of the most potent Eg5 inhibitor was investigated in vitro by apoptosis assay with Hoechst nuclear staining and flow cytometry. Immunofluorescence and immunostaining were used to elucidate the inhibitory mechanism. We evaluated the inhibitory effect in vivo in subcutaneous xenograft and metastatic cancer models.
  
  
  RESULTS
  Eg5 expression was increased in bladder cancer samples vs that in normal bladder epithelium samples. (S)-methoxy-trityl-L-cystein showed the strongest antiproliferative activity of the 5 Eg5 inhibitors and induced cell death after mitotic arrest via the caspase dependent apoptotic pathway. In vivo (S)-methoxy-trityl-L-cystein effectively suppressed tumor growth in subcutaneous and metastatic xenograft models. Survival time in (S)-methoxy-trityl-L-cystein treated nude mice was significantly longer than in untreated mice (p <0.001).
  
  
  CONCLUSIONS
  (S)-methoxy-trityl-L-cystein is a promising, novel anticancer agent for bladder cancer. Our data indicates its potential as effective therapy for metastatic bladder cancer.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Sentai
authors.initials: S
authors.lastname: Ding
authors.forename: Koji
authors.initials: K
authors.lastname: Nishizawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Jiajv
authors.initials: J
authors.lastname: Lv
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: C470243:KIF11 protein, human; D016547:Kinesins; D003545:Cysteine