title: Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition.
abstract: Cholangiocarcinoma (CCA), the common primary malignant tumor of bile duct epithelial cells, is unresponsive to most chemotherapeutic drugs. Diagnosis with CCA has a poor prognosis, and therefore urgently requires effective therapeutic agents. In the present study we investigated anti-cancer effects of andrographolide analogue 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) and its mechanism in human CCA cell line KKU-M213 derived from a Thai CCA patient. By 24h after exposure, the analogue 3A.1 exhibited a potent cytotoxic effect on KKU-M213 cells with an inhibition concentration 50 (IC50) of approximately 8.0µM. Analogue 3A.1 suppressed DNA topoisomerase II α (Topo II α) protein expression, arrested the cell cycle at sub G0/G1 phase, induced cleavage of DNA repair protein poly (ADP-ribose) polymerases-1 (PARP-1), and enhanced expression of tumor suppressor protein p53 and pro-apoptotic protein Bax. In addition, analogue 3A.1 induced caspase 3 activity and inhibited cyclin D1, CDK6, and COX-2 protein expression. These results suggest that andrographolide analogue 3A.1, a novel topo II inhibitor, has significant potential to be developed as a new anticancer agent for the treatment of CCA.
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Jintapat
authors.initials: J
authors.lastname: Nateewattana
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Suman
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Somrudee
authors.initials: S
authors.lastname: Reabroi
authors.affiliation: Department of Chemistry, Faculty of Science, Burapha University, Chonburi, Thailand.
authors.forename: Rungnapha
authors.initials: R
authors.lastname: Saeeng
authors.affiliation: Department of Chemistry, Faculty of Science, Burapha University, Chonburi, Thailand.
authors.forename: Sakkasem
authors.initials: S
authors.lastname: Kasemsook
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Arthit
authors.initials: A
authors.lastname: Chairoungdua
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Jittima
authors.initials: J
authors.lastname: Weerachayaphorn
authors.affiliation: Department of Biochemistry, Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Sopit
authors.initials: S
authors.lastname: Wongkham
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand. Electronic address: pawinee.pia@mahidol.ac.th.
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D017646:Organosilicon Compounds / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C000592143:19-tert-butyldiphenylsilyl-8,17-epoxyandrographolide; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C494826:BAX protein, human; D004268:DNA-Binding Proteins; D004224:Diterpenes; D017646:Organosilicon Compounds; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D004250:DNA Topoisomerases, Type II
keywords: Andrographolide analogue; Apoptosis; Cholangiocarcinoma; KKU-M213 cell line; Topoisomerase II α