Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells

Xiao Han; Junmin Zhang; Danfeng Shi; Yueting Wu; Ruijuan Liu; Tianyu Liu; Jianqiang Xu; Xiaojun Yao; Jianguo Fang

doi:10.1124/jpet.118.254862

Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells

J Pharmacol Exp Ther. 2019 May;369(2):212-222. doi: 10.1124/jpet.118.254862. Epub 2019 Feb 13.

Authors

Xiao Han¹, Junmin Zhang², Danfeng Shi¹, Yueting Wu¹, Ruijuan Liu¹, Tianyu Liu¹, Jianqiang Xu¹, Xiaojun Yao¹, Jianguo Fang³

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering (X.H., D.S., Y.W., T.L., X.Y., J.F.) and School of Pharmacy (J.Z., R.L.), Lanzhou University, Lanzhou, China; and School of Life Science and Medicine and Panjin Industrial Technology Institute, Dalian University of Technology, Panjin Campus, Panjin, China (J.X.).
² State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering (X.H., D.S., Y.W., T.L., X.Y., J.F.) and School of Pharmacy (J.Z., R.L.), Lanzhou University, Lanzhou, China; and School of Life Science and Medicine and Panjin Industrial Technology Institute, Dalian University of Technology, Panjin Campus, Panjin, China (J.X.) [email protected].
³ State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering (X.H., D.S., Y.W., T.L., X.Y., J.F.) and School of Pharmacy (J.Z., R.L.), Lanzhou University, Lanzhou, China; and School of Life Science and Medicine and Panjin Industrial Technology Institute, Dalian University of Technology, Panjin Campus, Panjin, China (J.X.) [email protected].

PMID: 30760494
DOI: 10.1124/jpet.118.254862

Abstract

Ibrutinib (IBT), the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase enzymes. Further study demonstrated that IBT can cause cellular reactive oxygen species elevation and induce cancer cell apoptosis. The discovery of a new target of IBT sheds light on better understanding its anticancer mechanisms and provides a theoretical foundation for its further use in clinical therapy.

Publication types

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

MeSH terms

Adenine / analogs & derivatives
Apoptosis / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Glutathione / metabolism
Humans
Molecular Docking Simulation
Molecular Targeted Therapy*
Piperidines
Protein Conformation
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / metabolism
Pyrazoles / pharmacology*
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Reactive Oxygen Species / metabolism
Sulfhydryl Compounds / metabolism
Thioredoxin-Disulfide Reductase / antagonists & inhibitors
Thioredoxin-Disulfide Reductase / chemistry
Thioredoxin-Disulfide Reductase / metabolism*

Substances

Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Reactive Oxygen Species
Sulfhydryl Compounds
ibrutinib
Thioredoxin-Disulfide Reductase
Glutathione
Adenine