CDDO-Me: A novel synthetic triterpenoid for the treatment of pancreatic cancer

Dorrah Deeb, Xiaohua Gao, Ali S. Arbab, Kenneth Barton, Scott A. Dulchavsky, Subhash C. Gautam

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1779-1793
Number of pages15
JournalCancers
Volume2
Issue number4
DOIs
StatePublished - Dec 1 2010

Fingerprint

Pancreatic Neoplasms
Sirolimus
Growth
TOR Serine-Threonine Kinases
Apoptosis
Oleanolic Acid
Caspase 8
Fluorescein-5-isothiocyanate
Mitochondrial Membrane Potential
Annexin A5
Cytochromes
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Caspase 3
Small Interfering RNA
Adenocarcinoma
Cell Line
Genes
Neoplasms

Keywords

  • Akt/mTOR signaling pathway
  • Apoptosis
  • CDDO-Me
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Deeb, D., Gao, X., Arbab, A. S., Barton, K., Dulchavsky, S. A., & Gautam, S. C. (2010). CDDO-Me: A novel synthetic triterpenoid for the treatment of pancreatic cancer. Cancers, 2(4), 1779-1793. https://doi.org/10.3390/cancers2041779

CDDO-Me : A novel synthetic triterpenoid for the treatment of pancreatic cancer. / Deeb, Dorrah; Gao, Xiaohua; Arbab, Ali S.; Barton, Kenneth; Dulchavsky, Scott A.; Gautam, Subhash C.

In: Cancers, Vol. 2, No. 4, 01.12.2010, p. 1779-1793.

Research output: Contribution to journalArticle

Deeb, D, Gao, X, Arbab, AS, Barton, K, Dulchavsky, SA & Gautam, SC 2010, 'CDDO-Me: A novel synthetic triterpenoid for the treatment of pancreatic cancer', Cancers, vol. 2, no. 4, pp. 1779-1793. https://doi.org/10.3390/cancers2041779
Deeb, Dorrah ; Gao, Xiaohua ; Arbab, Ali S. ; Barton, Kenneth ; Dulchavsky, Scott A. ; Gautam, Subhash C. / CDDO-Me : A novel synthetic triterpenoid for the treatment of pancreatic cancer. In: Cancers. 2010 ; Vol. 2, No. 4. pp. 1779-1793.
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