Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive to S-Trityl-L-Cysteine-Mediated Eg5 Inhibition

Wiltshire, C., Singh, B. L., Stockley, J., Fleming, J., Doyle, B., Barnetson, R., Robson, C. N., Kozielski, F. and Leung, H. Y. (2010) Docetaxel-Resistant Prostate Cancer Cells Remain Sensitive to S-Trityl-L-Cysteine-Mediated Eg5 Inhibition. Molecular Cancer Therapeutics, 9(6), pp. 1730-1739. (doi:10.1158/1535-7163.MCT-09-1103) (PMID:20515952)

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Abstract

Castrate-resistant prostate cancer remains a major clinical challenge. Due to the toxicity profile of taxane-based chemotherapy and treatment failure in some patients, novel agents with improved efficacy to side effect profiles are urgently needed. Eg5, a member of the kinesin-5 family, controls the formation of the bipolar spindle during cell division, and suppressed Eg5 function leads to mitotic arrest. S-Trityl-L-cysteine (STLC) is a novel Eg5-specific small-molecule inhibitor. Here, we report the first study to evaluate its use in prostate cancer. In a panel of prostate cancer cells, LNCaP and PC3 cells were the most and least sensitive to STLC treatment, with a 7.2-fold difference in their respective GI(50) values: 250 nmol/L and 1.8 mu mol/L. In LNCaP cells, treatment with either STLC or docetaxel resulted in transient G(2)-M arrest and subsequent caspase-mediated cell death. However, STLC- and docetaxel-treated PC3M cells have distinct fates: STLC induced a transient G(2)-M arrest, followed by polyploidy; in contrast, docetaxel-treated PC3M cells progressed to apoptosis after a transient G(2)-M arrest. Docetaxel-resistant LNCaP-derived (LDocR) cells respond to STLC in a similar manner to the parental cells. Although the docetaxel-resistant PC3M-derived (PDocR) cell line and its parental PC3M cells have similar GI(50) to STLC treatment, PDocR cells showed significantly more G(2)-M arrest and less apoptosis. Hence, although docetaxel-resistant prostate cancer cells remain responsive to Eg5 inhibition with STLC, there are key differences at the cell cycle level, which may have implication in future development. Mol Cancer Ther; 9(6); 1730-9. (C)2010 AACR

Item Type:Articles
Keywords:Agents, antimitotic drugs, apoptosis, cancer, cell-death, cell-line, cells, checkpoint, chemotherapy, death, development, distinct, efficacy, failure, family, inhibition, inhibitor, level, lines, mitotic kinesin Eg5, motor proteins, patient, patients, profile, proteomics, Scotland, screen, treatment.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kozielski, Professor Frank and Leung, Professor Hing and Wiltshire, Dr Carolyn and Fleming, Ms Janice and Doyle, Dr Brendan
Authors: Wiltshire, C., Singh, B. L., Stockley, J., Fleming, J., Doyle, B., Barnetson, R., Robson, C. N., Kozielski, F., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cancer Therapeutics
Publisher:American Association for Cancer Research
ISSN:1535-7163
ISSN (Online):1538-8514
Published Online:01 June 2010

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