title: Inhibition of cytochrome P450 2J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells.
abstract: Cytochrome P450 2J2 (CYP2J2) is highly expressed in human tumors and carcinoma cell lines, and has been implicated in the pathogenesis of human cancers. The aim of this study was to identify a compound that could inhibit the activity of CYP2J2, and to examine its anticancer activity. To identify CYP2J2 inhibitors, 10 terpenoids obtained from plants were screened using astemizole as a CYP2J2 probe substrate in human liver microsomes (HLMs). Of these, tanshinone IIA dose-dependently and non-competitively inhibited CYP2J2-mediated astemizole O-demethylation activity. Tanshinone IIA significantly decreased viability of human hepatoma HepG2 cells and SiHa cervical cancer cells; however, it was not cytotoxic against mouse hepatocytes. Furthermore, treatment of cells with tanshinone IIA significantly increased apoptotic cell death rate, as shown by the increase in Annexin V-stained cell populations, Bcl-2 associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio, and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage in HepG2 cells. Furthermore, the results of this study showed that tanshinone IIA significantly decreased HepG2 cell-based tumor growth in nude mice in a dose-dependent manner. On the other hand, the tanshinone IIA-induced apoptotic cell death rate was significantly attenuated by enhanced up-regulation of CYP2J2 expression. Thus, our data strongly suggest that tanshinone IIA exerts its anticancer effect by inhibiting CYP2J2 activity.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan, Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
authors.forename: Joong Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea.
authors.forename: Geun Hye
authors.initials: GH
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea.
authors.forename: Zhexue
authors.initials: Z
authors.lastname: Wu
authors.affiliation: College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Biology Education, College of Education, Pusan National University, Busan, Korea.
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Lark Kyun
authors.initials: LK
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea.
authors.forename: You-Mie
authors.initials: YM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea. Electronic address: vetmedic@knu.ac.kr.
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea. Electronic address: dstlkh@knu.ac.kr.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Lee
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016589:Astemizole / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D004305:Dose-Response Relationship, Drug; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013045:Species Specificity; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; C021751:tanshinone; D016589:Astemizole; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2
keywords: Anticancer; Apoptosis; Cytochrome P450 2J2; HepG2 cells; Tanshinone IIA