Paclitaxel in Ovarian Cancer

Extract

Less than half of ovarian cancers respond to treatment with paclitaxel. Targeted therapy is a promising approach to enhance the response of cancers to currently available cytotoxic drugs. To identify potential therapeutic targets, Le et al. (p. 1403 ) screened a library of silencing RNAs (siRNAs) targeting human protein kinases to identify those that regulate paclitaxel sensitivity in human ovarian cancer cells and validated their findings in vitro using independent siRNAs and dasatinib (an inhibitor of the Src family and Abl kinases) and in ovarian cancer xenograft–bearing mice treated with paclitaxel and/or dasatinib. They identified Src family and Abl kinases as modulators of paclitaxel sensitivity in human ovarian cancer cells. Dasatinib enhanced paclitaxel activity in vitro and in vivo by increasing apoptosis, inducing p27Kip1 protein expression, suppressing Bcl-2, and inhibiting Cdk1 at M phase in ovarian cancer cells. The authors conclude that siRNA- or dasatinib-mediated inhibition of Src family and Ablkinases enhances the sensitivity of ovarian cancer cells to paclitaxel through p27Kip1-mediated suppression of Bcl-2 and Cdk1 expression.