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Experimental and Molecular Therapeutics 12: New Targets, Agents, and Delivery Strategies

Bortezomib combined with docetaxel: Inhibition of efficacy via cell cycle arrest in experimental prostate cancer

Steven E. Canfield, Simon A. Williams and David J. McConkey
Steven E. Canfield
MD Anderson Cancer Center, Houston, TX
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Simon A. Williams
MD Anderson Cancer Center, Houston, TX
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David J. McConkey
MD Anderson Cancer Center, Houston, TX
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DOI:  Published April 2004
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Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

1502

The proteasome inhibitor bortezomib is currently being investigated in clinical trials for solid malignancies, including prostate cancer. It has been proposed that bortezomib might overcome drug resistance in cancer cells, yet combining bortezomib with some conventional chemotherapeutics has failed to show synergy. In fact, here we demonstrate that bortezomib inhibits docetaxel-induced apoptosis in LNCaP-Pro-5 prostate cancer cells. The opposite effect is seen with gemcitabine, and no effects are seen when bortezomib is combined with either drug in PC3M-Pro4 cells. We hypothesize that the inhibitory effects on docetaxel, which require cells to be in M phase, may be related to bortezomib’s effects on cell cycle progression. We therefore tested this hypothesis by comparing the effects of bortezomib with those of chemical cyclin-dependent kinase (cdk) inhibitors (roscovitine, olomucine). The prostate cancer cell used were LNCaP-Pro5 and PC3M-Pro4, orthotopically recycled aggressive variants of the parental lines. We incubated cells with bortezomib, docetaxel, gemcitabine, roscovitine, olomucine, and combinations for various periods of time in vitro, and we measured DNA fragmentation (characteristic of apoptosis) by propidium iodide staining and FACS analysis. We also characterized the effects of bortezomib on the cdk inhibitor p21 by immunoblotting. Finally, a direct role for p21 in bortezomib mediated cell cycle arrest and apoptosis suppression was determined by transfecting Pro5 cells with p21 cDNA, and by silencing p21 expression with siRNA. In Pro5 cells, combining bortezomib (10nM) with docetaxel (10ng/mL) inhibited apoptosis by 47% (p<0.001). Combining bortezomib with gemcitabine (10uM) increased apoptosis by 48% (p=0.01). Combinations in Pro4 cells showed no differences to drugs alone. Immunoblot studies confirmed that bortezomib stabilized the cdk inhibitor p21. Chemical cdk inhibitors also blocked docetaxel-induced apoptosis in Pro5 cells - roscovitine (50uM) by 37%, and olomucine (100uM) by 52%. Over expression of p21 in Pro5 cells via cDNA transfection inhibited docetaxel-induced apoptosis similarly to cells treated with bortezomib or the cdk inhibitors. Finally, silencing p21 in Pro5 cells abrogated the inhibitory effects of bortezomib on docetaxel-induced apoptosis. These findings suggest that in LNCaP Pro5 cells, bortezomib blocks the efficacy of docetaxel through stabilization of p21 and subsequent arrest of the cell cycle. This effect appears to be cell line-dependent and has important significance for designing and monitoring current and future clinical trials with bortezomib.

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April 2004
Volume 64, Issue 7 Supplement
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Bortezomib combined with docetaxel: Inhibition of efficacy via cell cycle arrest in experimental prostate cancer
Steven E. Canfield, Simon A. Williams and David J. McConkey
Cancer Res April 1 2004 (64) (7 Supplement) 346;

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Bortezomib combined with docetaxel: Inhibition of efficacy via cell cycle arrest in experimental prostate cancer
Steven E. Canfield, Simon A. Williams and David J. McConkey
Cancer Res April 1 2004 (64) (7 Supplement) 346;
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