Inhibition of cytochrome P450 2J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells

• Published in: European journal of pharmacology Vol. 764; pp. 480 - 488
• Main Authors: Jeon, Yu Jin, Kim, Joong Sun, Hwang, Geun Hye, Wu, Zhexue, Han, Ho Jae, Park, Soo Hyun, Chang, Woochul, Kim, Lark Kyun, Lee, You-Mie, Liu, Kwang-Hyeon, Lee, Min Young
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.10.2015
• Subjects: Animals; Anticancer; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Astemizole - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Survival - drug effects; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 2J2; Dealkylation; Diterpenes, Abietane - pharmacology; Dose-Response Relationship, Drug; Female; Hep G2 Cells; HepG2 cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Species Specificity; Tanshinone IIA; Time Factors; Transfection; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Tanshinone IIA; HepG2 cells; Cytochrome P450 2J2; Anticancer; Apoptosis
• DOI: 10.1016/j.ejphar.2015.07.047
• ISSN: 0014-2999

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.