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

Authors
 Yu Jin Jeon  ;  Joong Sun Kim  ;  Geun Hye Hwang  ;  Zhexue Wu  ;  Ho Jae Han  ;  Soo Hyun Park  ;  Woochul Chang  ;  Lark Kyun Kim  ;  You-Mie Lee  ;  Kwang-Hyeon Liu  ;  Min Young Lee 
Citation
 EUROPEAN JOURNAL OF PHARMACOLOGY, Vol.764 : 480-488, 2015 
Journal Title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN
 0014-2999 
Issue Date
2015
MeSH
Animals ; Antineoplastic Agents/pharmacology* ; 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* ; Dealkylation ; Diterpenes, Abietane/pharmacology* ; Dose-Response Relationship, Drug ; Female ; Hep G2 Cells ; Humans ; Liver Neoplasms/drug therapy* ; Liver Neoplasms/enzymology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Species Specificity ; Time Factors ; Transfection ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Keywords
Anticancer ; Apoptosis ; Cytochrome P450 2J2 ; HepG2 cells ; Tanshinone IIA
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S0014299915301722
DOI
10.1016/j.ejphar.2015.07.047
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Lark Kyun(김락균) ORCID logo https://orcid.org/0000-0001-5983-4470
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/157312
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