2. Academic Validation
  3. The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects

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

  • Cancer Res. 2017 Feb 15;77(4):926-936. doi: 10.1158/0008-5472.CAN-16-0987.
Xiaoyan Sun 1 2,  Weiguang Wang 3,  Jiao Chen 1 2,  Xueting Cai 1 2,  Jie Yang 1 2,  Yang Yang 1 2,  Huaijiang Yan 1 2,  Xiaolan Cheng 1 2,  Juan Ye 1 2,  Wuguang Lu 1 2,  Chunping Hu 1 2,  Handong Sun 3,  Jianxin Pu 4,  Peng Cao 5 2
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Targets and Drug Leads for Degenerative Diseases, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 2 Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China. pcao79@yahoo.com pujianxin@mail.kib.ac.cn.
  • 5 Key Laboratory of Drug Targets and Drug Leads for Degenerative Diseases, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. pcao79@yahoo.com pujianxin@mail.kib.ac.cn.
PMID: 28011619 DOI: 10.1158/0008-5472.CAN-16-0987
Abstract

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. Cancer Res; 77(4); 926-36. ©2016 AACR.

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