CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer

Cancers

Dorrah Deeb²  Xiaohua Gao²  Ali S. Arbab⁴  Kenneth Barton³  Scott A. Dulchavsky¹ 

[1] Department of General Surgery, Henry Ford Health System, Detroit, MI 48202, USA; E-Mails:;Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, USA; E-Mail:;Department of Diagnostic Radiology, Henry Ford Health System, Detroit, MI 48202, USA; E-Mail:

关键词: pancreatic cancer;    CDDO-Me;    apoptosis;    Akt/mTOR signaling pathway;   

DOI  :  10.3390/cancers2041779

来源: mdpi

【 摘 要 】

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.