PACLITAXEL-ASSOCIATED MULTIMININUCLEATION IS PERMITTED BY THE INHIBITION OF CASPASE ACTIVATION - A POTENTIAL EARLY STEP IN DRUG-RESISTANCE

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics ca using mitotic arrest, which leads to cell, death. However, in paclitax el-resistant tumor cells, treatment with paclitaxel induces abnormal p rogression through prophase resulting in a multimininucleated phenotyp e. Multimininucleation and subsequent polyploidization have been corre lated with paclitaxel resistance. Paclitaxel treatment of HeLa cells r esulted in cell death via typical activation of the apoptotic machiner y, whereas treatment of the relative paclitaxel-resistant prostate can cer cell line PC-3 induced an attenuated caspase activation and multim ininucleation. The multimininucleated phenotype could be mimicked in H eLa cells treated with paclitaxel and benzyloxycalbonyl-Val-Ala-Asp-fl uoromethylketone (z-VAD-fmk), a peptide caspase inhihitor. Interesting ly, we observed no discernible difference in the pattern of cdc-2 kina se activation or phosphorylation of bcl-2-like proteins in PC-3 and He La cells treated with paclitaxel, which demonstrated that these molecu les could not be used as indicators for the degree of caspase activati on. In this study, we establish a connection between relative paclitax el resistance, caspase attennation/inhibition, and the multimininuclea ted phenotype.