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Abstract

Volume 13, Issue 2 (March 2011) 13, 236–241; 10.1038/aja.2010.171

A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor

Nai-Dong Xing1,2, Sen-Tai Ding1,2, Ryoichi Saito1, Koji Nishizawa1, Takashi Kobayashi1, Takahiro Inoue1, Shinya Oishi3, Nobutaka Fujii3, Jia-Jv Lv2, Osamu Ogawa1 and Hiroyuki Nishiyama1

1 Department of Urology, Kyoto University, Graduate School of Medicine,, Kyoto 606-8507, Japan
2 Department of Urology, Provincial Hospital affiliated to Shandong University,, Jinan 250021, Shandong, China
3 Graduate School of Pharmaceutical Sciences, Kyoto University,, Kyoto 606-8507, Japan

Correspondence: Dr O Ogawa, (ogawao@kuhp.kyoto-u.ac.jp)

Received 24 July 2010; Revised 26 October 2010; Accepted 1 December 2010; Published online 7 February 2011

Abstract

Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-L-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer.

Keywords: Eg5 protein; prostate cancer; S-(methoxytrityl)-L-cysteine

Keywords: Eg5 protein; prostate cancer; S-(methoxytrityl)-L-cysteine

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