The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects

被引：54

作者：

Sun, Xiaoyan ^{[1
,2
]}

Wang, Weiguang ^{[3
]}

Chen, Jiao ^{[1
,2
]}

Cai, Xueting ^{[1
,2
]}

Yang, Jie ^{[1
,2
]}

Yang, Yang ^{[1
,2
]}

Yan, Huaijiang ^{[1
,2
]}

Cheng, Xiaolan ^{[1
,2
]}

Ye, Juan ^{[1
,2
]}

Lu, Wuguang ^{[1
,2
]}

Hu, Chunping ^{[1
,2
]}

Sun, Handong ^{[3
]}

Pu, Jianxin ^{[3
]}

Cao, Peng ^{[1
,2
]}

机构：

[1] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Key Lab Drug Targets & Drug Leads Degenerat Dis, Nanjing, Jiangsu, Peoples R China

[2] Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing, Jiangsu, Peoples R China

[3] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China

来源：

CANCER RESEARCH | 2017年 / 77卷 / 04期

基金：

中国国家自然科学基金;

关键词：

B INDUCES APOPTOSIS; CANCER-CELLS; NEOPLASTIC-CELLS; SMALL-MOLECULE; EXPRESSION; SYSTEM; MECHANISMS; CARCINOMA; REDUCTASE; STRESS;

D O I：

10.1158/0008-5472.CAN-16-0987

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol- based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. (C)2016 AACR.

引用

页码：926 / 936

页数：11

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