AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance

Hui Zhang; Yi-Jun Wang; Yun-Kai Zhang; De-Shen Wang; Rishil J Kathawala; Atish Patel; Tanaji T Talele; Zhe-Sheng Chen; Li-Wu Fu

doi:10.1016/j.canlet.2014.04.008

AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance

Cancer Lett. 2014 Aug 1;350(1-2):61-8. doi: 10.1016/j.canlet.2014.04.008. Epub 2014 Apr 18.

Authors

Hui Zhang¹, Yi-Jun Wang², Yun-Kai Zhang², De-Shen Wang¹, Rishil J Kathawala², Atish Patel², Tanaji T Talele², Zhe-Sheng Chen³, Li-Wu Fu⁴

Affiliations

¹ Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
² Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
³ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: chenz@stjohns.edu.
⁴ Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: fulw@mail.sysu.edu.cn.

PMID: 24747122
DOI: 10.1016/j.canlet.2014.04.008

Abstract

AST1306, an inhibitor of EGFR and ErbB2, is currently in phase I of clinical trials. We evaluated the effect of AST306 on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters. We found that AST1306 significantly sensitized the ABC subfamily G member 2 (ABCG2)-overexpressing cells to ABCG2 substrate chemotherapeutics. AST1306 significantly increased intracellular accumulation of [(3)H]-mitoxantrone in ABCG2-overexpressing cells by blocking ABCG2 efflux function. Moreover, AST1306 stimulated the ATPase activity of ABCG2. Homology modeling predicted the binding conformation of AST1306 to be within the transmembrane region of ABCG2. In conclusion, AST1306 could notably reverse ABCG2-mediated MDR.

Keywords: ABCG2; AST1306; ATP-binding cassette transporters; Multidrug resistance.

Publication types

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

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors*
Acrylamides / pharmacology*
Antineoplastic Agents / pharmacology
Biological Transport / drug effects*
Cell Line, Tumor
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
ErbB Receptors / antagonists & inhibitors
Humans
Mitoxantrone / chemistry
Molecular Docking Simulation
Neoplasm Proteins / antagonists & inhibitors*
Protein Kinase Inhibitors / pharmacology
Quinazolines / pharmacology*
Receptor, ErbB-2 / antagonists & inhibitors

Substances

ABCG2 protein, human
AST 1306
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Acrylamides
Antineoplastic Agents
Neoplasm Proteins
Protein Kinase Inhibitors
Quinazolines
Mitoxantrone
EGFR protein, human
ERBB2 protein, human
ErbB Receptors
Receptor, ErbB-2