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Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-κB/mTOR signaling proteins and anti-apoptotic Bcl-2.

Abstract
Lack of effective therapeutics for pancreatic cancer at the present time underscores the dire need for safe and effective agents for the treatment of this malignancy. In the present study, we have evaluated the anticancer activity and the mechanism of action of pristimerin (PM), a quinonemethide triterpenoid, against MiaPaCa-2 and Panc-1 pancreatic ductal adenocarcinoma (PDA) cell lines. Treatment with PM inhibited the proliferation and induced apoptosis in both cell lines as characterized by the increased Annexin V-binding and cleavage of PARP-1 and procaspases -3, -8 and -9. PM also induced mitochondrial depolarization and the release of cytochrome c from the mitochondria. The induction of apoptosis by PM was associated with the inhibition of the pro-survival Akt, NF-κB and mTOR signaling proteins and their downstream intermediaries such as Foxo-3α and cyclin D1 (Akt); Cox-2 and VEGF (NF-κB); p-S6K1 and p-4E-BP1 (mTOR) as well as PKCε. Treatment with PM also inhibited the expression of anti-apoptotic Bcl-2 and survivin but not Bcl-xL. The downregulation of Bcl-2 by PM was not due to proteasomal or lysosomal proteolytic degradation of Bcl-2, since treatment with PM in the presence of proteasomal inhibitors MG132 or lactacystin (LAC) or calpain inhibitor MG101 failed to block the downregulation of Bcl-2 by PM. On the other hand, RT-PCR analysis showed the inhibition of Bcl-2 mRNA by PM in a dose-related manner, indicating that inhibition of Bcl-2 by PM is mediated through the suppression of Bcl-2 gene expression. Thus, the mechanistic understanding of the antitumor activity of pristimerin could facilitate in vivo efficacy studies of pristimerin for pancreatic cancer.
AuthorsDorrah Deeb, Xiaohua Gao, Yong Bo Liu, Kirit Pindolia, Subhash C Gautam
JournalInternational journal of oncology (Int J Oncol) Vol. 44 Issue 5 Pg. 1707-15 (May 2014) ISSN: 1791-2423 [Electronic] Greece
PMID24603988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • NF-kappa B
  • Pentacyclic Triterpenes
  • Proto-Oncogene Proteins c-bcl-2
  • Triterpenes
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • celastrol
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • In Vitro Techniques
  • Mitochondria (physiology)
  • NF-kappa B (genetics, metabolism)
  • Pancreatic Neoplasms (pathology)
  • Pentacyclic Triterpenes
  • Proto-Oncogene Proteins c-akt (genetics, metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
  • Signal Transduction (drug effects)
  • TOR Serine-Threonine Kinases (genetics, metabolism)
  • Triterpenes (pharmacology)

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