Synthetic Oleanane Triterpenoid, CDDO-Me, Induces Apoptosis in Ovarian Cancer Cells by Inhibiting Prosurvival AKT/NF-κB/mTOR Signalling

Synthetic oleanane triterpenoids are novel agents which have shown strong antitumorigenic activity against a wide range of cancer types in vitro. The objective of the present study was to determine the anticancer activity of methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) derived from CDDO, a synthetic analog of oleanolic acid, and its mechanism of action in killing of human ovarian cancer cells. CDDO-Me strongly inhibited the growth of ovarian cancer cells by inducing apoptosis characterized by increased annexin V binding, cleavage of poly (ADP-ribose) polymerase (PARP-I) and procaspases-3, -8 and -9. In addition, CDDO-Me induced mitochondrial depolarization. Western blot analysis showed inhibition of prosurvival (antiapoptotic) phospho-AKT (p-AKT), nuclear factor kappa B (NF-kappa B) (p65) and phospho- mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with CDDO-Me. Abrogation of AKT which regulates both NF-kappa B and mTOR increased the sensitivity of tumor cells to CDDO-Me. Thus, these data showing strong growth-inhibitory and apoptosis-inducing activity of CDDO-Me for ovarian cancer cells through the inhibition of AKT/ NF-kappa B/mTOR signaling pathway provide basis for evaluation of CDDO-Me for ovarian cancer.