Regorafenib Antagonizes BCRP-mediated Multidrug Resistance in Colon Cancer

Overview

Journal Cancer Lett

Specialty Oncology

Date 2018 Nov 6

PMID 30392788

Citations 22

Authors

Yun-Kai Zhang

Yi-Jun Wang

Zi-Ning Lei

Guan-Nan Zhang

Xiao-Yu Zhang

De-Shen Wang

Sweilem B Al-Rihani

Suneet Shukla

Suresh V Ambudkar

Amal Kaddoumi

Zhi Shi

Zhe-Sheng Chen

Affiliations

Soon will be listed here.

Abstract

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.

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