Wortmannin enhances cisplatin-induced apoptosis in human ovarian cancer cells in vitro.

OBJECTIVE The PI3K/Akt signaling pathway is constitutively activated in some ovarian cancers; when activated, it promotes invasion and inhibits chemotherapy-mediated apoptosis in cancer cells. The fungal metabolite wortmannin is the currently known inhibitors that show fairly high specificity for PI3K.We examined whether PI3K/Akt activity correlates with invasion and apoptotic resistance to chemotherapy in cultured human ovarian cancer cells, and whether inhibition of PI3K/Akt by wortmannin inhibits invasion and enhances cisplatin-induced apoptosis in cultured human ovarian cancer cells. MATERIALS AND METHODS The cisplatin-sensitive A2780 ovarian adenocarcinoma cell line and its daughter line, A2780cis was evaluated for basal Akt activity. Chemotherapy-induced cell death was evaluated following down-regulation of Akt activity by wortmannin treatment or upregulation of Akt activity by myr-Akt treatment. Invasion and migration were assessed using Boyden chamber assays RESULTS Inhibiting or activation of PI3K/Akt signaling pathway by wortmannin had little effect on the basal level of apoptosis in ovarian cancer cells, but increased the apoptotic effect of chemotherapy in A2780cis cells, decreased the apoptotic effect of chemotherapy in cisplatin-sensitive A2780 cells. Cisplatin resistant cells display increased potential for migration and invasion. CONCLUSIONS The antiapoptotic effect of AKT activation in ovarian cancer cells confer invasive ability and resistance to apoptosis. Wortmannin is as adjuncts to conventional chemotherapy in the treatment of ovarian cancer.