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The role of thioredoxin reductase and glutathione reductase in plumbagin-induced, reactive oxygen species-mediated apoptosis in cancer cell lines

Authors
 Geun Hye Hwang  ;  Jung Min Ryu  ;  Yu Jin Jeon  ;  Joonhyeok Choi  ;  Ho Jae Han  ;  You-Mie Lee  ;  Sangkyu Lee  ;  Jong-Sup Bae  ;  Jong-Wha Jung  ;  Woochul Chang  ;  Lark Kyun Kim  ;  Jun-Goo Jee  ;  Min Young Lee 
Citation
 EUROPEAN JOURNAL OF PHARMACOLOGY, Vol.765 : 384-393, 2015 
Journal Title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN
 0014-2999 
Issue Date
2015
MeSH
Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/pharmacology* ; Apoptosis/drug effects ; Apoptosis/physiology* ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Glutathione Reductase/physiology* ; Hep G2 Cells ; Humans ; Naphthoquinones/chemistry ; Naphthoquinones/pharmacology* ; Reactive Oxygen Species/metabolism* ; Thioredoxin-Disulfide Reductase/physiology*
Keywords
Anticancer ; Glutathione reductase ; Plumbagin ; Reactive oxygen species ; Thioredoxin reductase
Abstract
Plumbagin is a secondary metabolite that was first identified in the Plumbago genus of plants. It is a naphthoquinone compound with anti-atherosclerosis, anticancer, anti-inflammatory, antimicrobial, contraceptive, cardiotonic, immunosuppressive, and neuroprotective activities. However, the mechanisms of plumbagin's activities are largely unknown. In this study, we examined the effect of plumbagin on HepG2 hepatocellular carcinoma cells as well as LLC lung cancer cells, SiHa cervical carcinoma cells. Plumbagin significantly decreased HepG2 cell viability in a dose-dependent manner. Additionally, treatment with plumbagin significantly increased the Bax/Bcl-2 ratio and caspase-3/7 activity. Using the similarity ensemble approach (SEA)-a state-of-the-art cheminformatic technique-we identified two previously unknown cellular targets of plumbagin: thioredoxin reductase (TrxR) and glutathione reductase (GR). This was then confirmed using protein- and cell-based assays. We found that plumbagin was directly reduced by TrxR, and that this reduction was inhibited by the TrxR inhibitor, sodium aurothiomalate (ATM). Plumbagin also decreased the activity of GR. Plumbagin, and the GR inhibitor sodium arsenite all increased intracellular reactive oxygen species (ROS) levels and this increase was significantly attenuated by pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) in HepG2 cells. Plumbagin increased TrxR-1 and heme oxygenase (HO)-1 expression and pretreatment with NAC significantly attenuated the plumbagin-induced increase of TrxR-1 and HO-1 expression in HepG2 cells, LLC cells and SiHa cells. Pretreatment with NAC significantly prevented the plumbagin-induced decrease in cell viability in these cell types. In conclusion, plumbagin exerted its anticancer effect by directly interacting with TrxR and GR, and thus increasing intracellular ROS levels.
Full Text
https://www.sciencedirect.com/science/article/pii/S0014299915302326
DOI
10.1016/j.ejphar.2015.08.058
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/22282913/157313
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