The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide.

Qiu-Xu Teng,Zi-Ning Lei,John Wurpel,Zuodong Qin,Dong-Hua Yang,Xiaofang Luo,Jing-Quan Wang

doi:10.3390/cancers12071963

Abstract

The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.

Highlights

The incidence of cancer has increased as a result of growing population, aging, and other risk factors [1,2]
No significant change in the drug resistant profile of cisplatin, which is not a substrate of ABCB1 transporter, in both drug-selected and transfected ABCB1-overexpression cells was observed with or without the peptide. These results indicated that peptide XH-14C could reverse multidrug resistance (MDR) of cancer cells mediated by
ATPase activity concentration-dependent manner, a concentration of μM, which is much lower than thethe reversal in a concentration-dependent manner, a concentration of 0.05 μM, which is much lower than effect concentration in in thethe reversal assay, was calculated as as thethe essential concentration for half reversal effect concentration reversal assay, was calculated essential concentration simulation of. These results suggested that may for half simulation of ABCB1 ATPase activity. These results suggested that XH-14C may reversereverse by affecting the ATPase through interaction with ABCB1

Summary

Introduction

The incidence of cancer has increased as a result of growing population, aging, and other risk factors [1,2]. As MDR refers to the resistance of cancer cells to various different structural and functional chemotherapeutic drugs [4], it is a major factor of failure of cancer chemotherapy [5]. The mechanisms of MDR could be classified into several categories, with the major one being the enhancement of drug efflux by transporters on cancer cell membranes [6]. The ATP-binding cassette (ABC) transporter family is a protein superfamily with 49 different members categorized by gene sequence and structural similarities [3]. They are the main cell membrane transporters and are organized into seven subfamilies [7].

Methods

Discussion

Conclusion