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Mol Cancer Ther. 2006 Aug;5(8):2043-50.

Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells.

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  • 1Department of Urology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, USA.

Abstract

Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation. The effects of bortezomib were associated with accumulation of p21 and mimicked by chemical CDK inhibitors or by transfecting cells with a small interfering RNA construct specific for CDK1. Transient transfection with p21 also inhibited docetaxel-induced apoptosis; conversely, p21 silencing reversed the antagonistic effects of bortezomib on docetaxel-induced apoptosis. Together, our data show that bortezomib interferes with docetaxel-induced apoptosis via a p21-dependent mechanism that is associated with CDK1 inhibition. These observations may have important implications for the ongoing bortezomib-docetaxel combination trials as well as trials using bortezomib and other cell cycle-sensitive agents.

PMID:
16928825
DOI:
10.1158/1535-7163.MCT-05-0437
[PubMed - indexed for MEDLINE]
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