An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy

Jiayu Zhu; Huihui Wang; Feng Chen; Jingqi Fu; Yuanyuan Xu; Yongyong Hou; Henry H Kou; Cheng Zhai; M Bud Nelson; Qiang Zhang; Melvin E Andersen; Jingbo Pi

doi:10.1016/j.freeradbiomed.2016.09.010

An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy

Free Radic Biol Med. 2016 Oct:99:544-556. doi: 10.1016/j.freeradbiomed.2016.09.010. Epub 2016 Sep 12.

Authors

Jiayu Zhu¹, Huihui Wang¹, Feng Chen², Jingqi Fu¹, Yuanyuan Xu³, Yongyong Hou¹, Henry H Kou¹, Cheng Zhai¹, M Bud Nelson⁴, Qiang Zhang⁵, Melvin E Andersen⁶, Jingbo Pi⁷

Affiliations

¹ Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
² Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Road, Heping Area, Shenyang 110001, China.
³ Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. Electronic address: yyxu@cmu.edu.cn.
⁴ MedBlue Incubator, Inc., Research Triangle Park, NC 27709, USA.
⁵ Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
⁶ Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, ScitoVation, LLC, NC 27709, USA LLC.
⁷ Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. Electronic address: jbpi@cmu.edu.cn.

PMID: 27634172
DOI: 10.1016/j.freeradbiomed.2016.09.010

Abstract

The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes in response to oxidative and xenobiotic stress. A large number of Nrf2-antioxidant response element (ARE) activators have been screened for use as chemopreventive agents in oxidative stress-related diseases and even cancer. However, constitutive activation of Nrf2 occurs in a variety of cancers. Aberrant activation of Nrf2 is correlated with cancer progression, chemoresistance, and radioresistance. In this review, we examine recent studies of Nrf2-ARE inhibitors in the context of cancer therapy. We enumerate the possible Nrf2-inhibiting mechanisms of these compounds, their effects sensitizing cancer cells to chemotherapeutic agents, and the prospect of applying them in clinical cancer therapy.

Keywords: ARE; Cancer therapy; Chemoresistance; Inhibitor; Nrf2.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antioxidant Response Elements / drug effects*
Antitubercular Agents / pharmacology
Cullin Proteins / genetics
Cullin Proteins / metabolism
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Flavonoids / pharmacology
Gene Expression Regulation, Neoplastic*
Humans
Hypoglycemic Agents / pharmacology
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
NF-E2-Related Factor 2 / antagonists & inhibitors*
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Oxidative Stress / drug effects
Signal Transduction
Vitamins / pharmacology

Substances

Antineoplastic Agents
Antitubercular Agents
CUL3 protein, human
Cullin Proteins
Flavonoids
Hypoglycemic Agents
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
NFE2L2 protein, human
Vitamins