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)
Full text not currently available from Enlighten.
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 > School 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 |
University Staff: Request a correction | Enlighten Editors: Update this record