title: 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.affiliation: Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Haoxin
authors.initials: H
authors.lastname: Zhou
authors.forename: Guang
authors.initials: G
authors.lastname: Jia
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Zhuoxin
authors.initials: Z
authors.lastname: Cheng
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; D003841:Deoxycytidine; D004247:DNA; C050414:celastrol; D000093542:Gemcitabine