Synthetic oleanane triterpenoid, CDDO-Me, induces apoptosis in ovarian cancer cells by inhibiting prosurvival AKT/NF-κB/mTOR signaling.

Abstract

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-1) 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-κB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with CDDO-Me. Abrogation of AKT which regulates both NF-κB 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-κB/mTOR signaling pathway provide basis for evaluation of CDDO-Me for ovarian cancer.

• Authors: Xiaohua Gao, Yongbo Liu, Dorrah Deeb, Ali S Arbab, Austin M Guo, Scott A Dulchavsky, Subhash C Gautam
• Journal: Anticancer research (Anticancer Res) Vol. 31 Issue 11 Pg. 3673-81 (Nov 2011) ISSN: 1791-7530 [Electronic] Greece
• PMID: 22110186 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Oleanolic Acid
• bardoxolone methyl
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mitochondria (drug effects)
• NF-kappa B (metabolism)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (metabolism)