PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation

Background: Since ovarian cancer is associated with high frequency of p53 mutation, the availability of p53 reactivation and induction of massive apoptosis (PRIMA-1) offers a possible new therapeutic strategy for overcoming this devastating disease. Although Akt activation is believed to be a determinant in chemoresistance in ovarian cancer, whether Akt plays a role in regulating the effectiveness of PRIMA-1 in sensitizing chemoresistant ovarian cancer cells with p53 mutation to cisplatin (CDDP), remains to be determined. Methods: In the present studies, we examined the influence of Akt down-regulation following dominant-negative (DN-Akt) expression on the ability of PRIMA-1 (0-10 mu M) to facilitate CDDP (0-10 mu M)-induced apoptosis in p53-mutated chemoresistant ovarian cancer cells (A2780cp). Results: Apoptosis rate was significantly higher at the combined treatment of low PRIMA-1 concentrations (0.156 - 0.938 mu M) plus CDDP (10 mu M) in the DN-Akt groups than control (p<0.001). Apoptosis in cells treated with PRIMA-1 (0.156 mu M) and CDDP treatment (10 mu M) was significantly suppressed by p53-siRNA. PRIMA-1 increased phospho-p53 (Ser15) content in Akt down-regulated cells treated with CDDP. Conclusions: These results demonstrate that PRIMA-1 can sensitize chemoresistant ovarian cancer cells with p53 mutation to CDDP when Akt is down-regulated, and the action of PRIMA-1 is associated with p53 activation. Our findings raise the possibility that PRIMA-1 may be useful candidate for adjuvant therapy with CDDP in chemoresistant ovarian cancer with p53 mutation when Akt is down-regulated.