Driving p53 response to bax activation greatly enhances sensitivity to taxol by inducing massive apoptosis

The proapoptotic gene bar is one of the downstream effecters of p53. The p5 3 binding site in the bar promoter is less responsive to p53 than the one i n the growth arrest mediating gene p21. We introduced the bar gene under th e control of 13 copies of a strong p53 responsive element into two ovarian cancer cell lines. The clones expressing bar under the control of p53 obtai ned from the wild-type (wt) p53-expressing cell line A2780 were much more s ensitive (500- to 1000-fold) to the anticancer agent taxol than the parent cell line, with a higher percentage of cells undergoing apoptosis after dru g treatment that was clearly p53-dependent and bax-mediated. Xenografts est ablished in nude mice from one selected clone (A2780/C3) were more responsi ve to taxol than the parental line and the apoptotic response of A2780/C3 t umors was also increased after treatment. Introduction of the same plasmid into the p53 null SKOV3 cell line did not alter the sensitivity to taxol or the induction of apoptosis. In conclusion, driving the p53 response (after taxol treatment) by activating the bar gene rather than the p21 gene resul ts in induction of massive apoptosis, in vitro and in vivo, and greatly enh ances sensitivity to the drug.