title: KUD773, a phenylthiazole derivative, displays anticancer activity in human hormone-refractory prostate cancers through inhibition of tubulin polymerization and anti-Aurora A activity.
abstract: BACKGROUND
  Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded.
  
  
  RESULTS
  KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr(161) (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr(15) (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.
  
  
  CONCLUSIONS
  The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan. d98423007@ntu.edu.tw.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan. spliu@ntuh.gov.tw.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan. juiling221@hotmail.com.
authors.forename: Jui-Ling
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan. tsuanhsu@nhri.org.tw.
authors.forename: John Ta
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Department of Medicinal Chemistry, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russian Federation. kudr@med.chem.msu.ru.|Institute of Physiologically Active Compounds, Russian Academy of Sciences, Moscow region, Russian Federation. kudr@med.chem.msu.ru.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Kudryavtsev
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan. jhguh@ntu.edu.tw.
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D008297:Male; D058105:Polymerization / Q000187:drug effects; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; C576917:AURKA protein, human; D064096:Aurora Kinase A