Phenethyl isothiocyanate (PEITC) inhibits growth of ovarian cancer cells by inducing apoptosis: Role of caspase and MAPK activation

Objective. Epithelial ovarian cancer has the highest mortality rate among gynecologic cancers. Chemotherapy is an essential component of its treatment. While isothiocyanates are known to possess chemopreventive effects against various cancers, yet little is known about their chemotherapeutic potential in ovarian cancer (OC). In the present study, we examined the antiproliferative and apoptotic effect of phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate on OVCAR-3 cells. Methods. Cytotoxic activity of PEITC on OVCAR-3 cells was determined using cell proliferation, apoptosis (DNA fragmentation and TUNEL assay) and caspase-activation studies. The role of PARP-1, Bax, and Bcl-2 in apoptosis was analyzed by Western blotting. Activation of JNK1/2, p38, Akt, ERK1/2, and c-Myc was examined by immunoblotting. Specific inhibitors of caspases, JNK1/2, p38, and MEK were used to corroborate these data. Results. PEITC was cytotoxic to OVCAR-3 cells, and inhibited proliferation in a dose-dependent fashion (IC50 = 23.2 mu M). PEITC induced apoptosis by activating caspase-3 and -9, without capsase-8 activation. Anti-apoptotic Bcl-2 levels were suppressed while pro-apoptotic Bax levels were enhanced. PEITC suppressed activation of Akt, ERK1/2, and the expression of transcription factor c-Myc, while simultaneously activating pro-apoptotic p38 and JNK1/2. Specific inhibitors of caspase-3 and -9, JNK1/2, and p38 reversed the cytotoxic effect of PEITC. Conclusions. These findings demonstrate that PEITC exhibits cytotoxicity towards OVCAR-3 cells and induces apoptosis via caspase-9 and -3 pathways. PEITC inhibits Akt, ERK1/2 survival signaling, and c-Myc while simultaneously activating pro-apoptotic p38 and JNK1/2. Systematic preclinical and clinical trials with PEITC in ovarian cancer are indicated. (c) 2006 Elsevier Inc. All rights reserved.