title: Oridonin induces apoptosis in SW1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 MAPK.
abstract: Oridonin, an active component isolated from Rabdosia rubescens, has been reported to exhibit antitumor effects. In the present study, we evaluated the antitumor activity and the mechanisms of action of oridonin in pancreatic cancer. Oridonin treatment significantly induced apoptotic cell death in SW1990 pancreatic cancer cells in a dose-dependent manner. Additionally, cell apoptosis was markedly inhibited by PFT α (pifithrin α), a p53-specific inhibitor, which was applied to evaluate the function of p53, showing that p53 was responsible for the cytotoxity of oridonin. Moreover, oridonin increased the expression of p-p53 with a concomitant increase in p21 in the SW1990 cells. Following treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor), the cytotoxity of oridonin was not influenced by JNK (SP600125) and ERK (PD98059), but these effects were opposite to the cytotoxity of oridonin observed with SP203580 treatment. These findings confirmed that orodonin-induced apoptosis was p38-dependent, but JNK- and ERK-independent. Furthermore, the activation of the p38 kinase promoted the activation of p53 and its downstream target p21, and further caused caspase-9 and -3 activation, as demonstrated by evidence showing that the p38 inhibitor SB203580 not only blocked the phosphorylation of p38 but also reduced the activation of p53, p21 and caspase-9 and -3. Collectively, these results suggest that p53-dependent and caspase-dependent induction of p38 MAPK directly participates in apoptosis induced by oridonin.
authors.affiliation: Department of Anorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, P.R. China.
authors.forename: He-Qi
authors.initials: HQ
authors.lastname: Bu
authors.affiliation: Department of Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, P.R. China.
authors.forename: Dian-Lei
authors.initials: DL
authors.lastname: Liu
authors.affiliation: Department of Oncological Surgery, Zhejiang Cancer Hospital, Hangzhou, P.R. China.
authors.forename: Wei-Tian
authors.initials: WT
authors.lastname: Wei
authors.affiliation: Department of Surgery, the Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, P.R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgery, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, P.R. China.
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Cui
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D037602:Isodon / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D028321:Plant Preparations / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D052160:Benzothiazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D045786:Diterpenes, Kaurane; D005419:Flavonoids; D007093:Imidazoles; D028321:Plant Preparations; D011725:Pyridines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C011959:oridonin; C432165:pyrazolanthrone; D014050:Toluene; C121565:pifithrin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one