Pristimerin causes G1 arrest, induces apoptosis, and enhances the chemosensitivity to gemcitabine in pancreatic cancer cells.

Abstract

Despite rapid advances in chemotherapy and surgical resection strategies, pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5%. Therefore, novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed. The aim of this study was to investigate the effect of pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells, BxPC-3, PANC-1 and AsPC-1, in both monotherapy and in combination with gemcitabine. Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose- and time-dependent manner. Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins (D1 and E) and cyclin-dependent kinases (cdk2, cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27. Pristimerin treatment also resulted in apoptotic cell death, cleavage of caspase-3, modulation in the expressions of Bcl-2 family proteins, inhibition of the translocation and DNA-binding activity of NF-κB. In addition, pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells, at least in part, by inhibiting constitutive as well as gemcitabine-induced activation of NF-κB in both its DNA-binding activity and transcriptional activity. Taken together, these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer.

• Authors: Yongwei Wang, Yinan Zhou, Haoxin Zhou, Guang Jia, Ji Liu, Bing Han, Zhuoxin Cheng, Hongchi Jiang, Shangha Pan, Bei Sun
• Journal: PloS one (PLoS One) Vol. 7 Issue 8 Pg. e43826 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22952775 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Antineoplastic Agents
• NF-kappa B
• Pentacyclic Triterpenes
• Proto-Oncogene Proteins c-bcl-2
• Triterpenes
• Deoxycytidine
• DNA
• celastrol
• Gemcitabine

Topics

• Anticarcinogenic Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Synergism
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• NF-kappa B (metabolism)
• Pancreatic Neoplasms (pathology)
• Pentacyclic Triterpenes
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Triterpenes (pharmacology)
• Gemcitabine