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Title: Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition
Authors: Jintapat Nateewattana
Suman Dutta
Somrudee Reabroi
Rungnapha Saeeng
Sakkasem Kasemsook
Arthit Chairoungdua
Jittima Weerachayaphorn
Sopit Wongkham
Pawinee Piyachaturawat
Mahidol University
Burapha University
Khon Kaen University
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 15-Jan-2014
Citation: European Journal of Pharmacology. Vol.723, No.1 (2014), 148-155
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 24 h after exposure, the analogue 3A.1 exhibited a potent cytotoxic effect on KKU-M213 cells with an inhibition concentration 50 (IC50) of approximately 8.0 μM. 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. © 2013 Elsevier B.V.
ISSN: 18790712
Appears in Collections:Scopus 2011-2015

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