KUD773, a phenylthiazole derivative, displays anticancer activity in human hormone-refractory prostate cancers through inhibition of tubulin polymerization and anti-Aurora A activity.
| Autor: | Yu CC; School of Pharmacy, National Taiwan University, Taipei, Taiwan. d98423007@ntu.edu.tw., Liu SP; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan. spliu@ntuh.gov.tw., Hsu JL; School of Pharmacy, National Taiwan University, Taipei, Taiwan. juiling221@hotmail.com., Hsu JT; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan. tsuanhsu@nhri.org.tw., Kudryavtsev KV; 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., Guh JH; School of Pharmacy, National Taiwan University, Taipei, Taiwan. jhguh@ntu.edu.tw. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of biomedical science [J Biomed Sci] 2015 Jan 07; Vol. 22, pp. 2. Date of Electronic Publication: 2015 Jan 07. |
| DOI: | 10.1186/s12929-014-0107-x |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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