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Research Articles: Therapeutics

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

Departments of ¹ Urology and ² Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Correspondence: David McConkey, Department of Cancer Biology-173, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8591; Fax: 713-792-8747. E-mail: dmcconke{at}mdanderson.org

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. [Mol Cancer Ther 2006;5(8):2043–50]

Note: Current address for S.E. Canfield: Department of Urology, University of Texas-Houston School of Medicine, P.O. Box 20708, Houston, TX 77225-0708, E-mail: Steven.Canfield{at}uth.tmc.edu; S.A. Williams: Oncology Center, Division of Experimental Therapeutics, Johns Hopkins University, CRB I, 1650 Orleans Street, Baltimore, MD 21231, E-mail: swilli87{at}jhmi.edu.

³ S.A Williams and D.J. McConkey, unpublished observation.

⁴ A. Kwan, unpublished observation.

Received 10/18/05; revised 4/25/06; accepted 5/31/06.

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