Overexpression of ABCC1 Confers Drug Resistance to Betulin.

Jing-Quan Wang,Yuqi Yang,Jing Li,Xuan-Yu Chen,Zhuo-Xun Wu,Zhe-Sheng Chen

doi:10.3389/fonc.2021.640656

Jing-Quan Wang, Yuqi Yang + Show 4 more

Open Access

https://doi.org/10.3389/fonc.2021.640656

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Abstract

Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.

Highlights

To date, many drugs have originated from natural products, including vincristine, vinblastine, doxorubicin, and paclitaxel all have the potential to inhibit tumor progression [1]
AThe half-maximal inhibitory concentration (IC50) values are showed as mean ± SD from at least three independent experiments performed in triplicate. bResistance fold (RF) was calculated by dividing the IC50 values of drug-sensitive cells with MK571 or cells expressed ATP-binding cassette subfamily C member 1 (ABCC1) with or without MK571 by the IC50 values of their corresponding parental cells without MK571
Efficacy of betulin was restricted in cells expressing ABCC1 as evidenced by higher IC50 values in multidrug resistance (MDR) cells mediated by ABCC1 compared to their corresponding drug-sensitive cell line counterparts

Summary

Introduction

Many drugs have originated from natural products, including vincristine, vinblastine, doxorubicin, and paclitaxel all have the potential to inhibit tumor progression [1]. Vincristine, vinblastine, doxorubicin, and paclitaxel can be transported by ABC sub-family B member 1 (ABCB1, multidrug resistance protein 1/MDR1, P-glycoprotein/P-gp) [3]; whereas, vincristine, vinblastine, and doxorubicin are substrate drugs of ABC sub-family C member 1 (ABCC1, multidrug resistance protein 1/MRP1) [4]. The 190 kDa MRP1, located in human chromosome locus p13.11, was firstly isolated from doxorubicin-resistance small cell lung cancer line H69AR, and was found to be associated with MDR in 1992 [5, 6]. The protein structure of MRP1 has three membrane-spanning domains (MSDs), and two nucleotide-binding domains (NBDs) [7]. The NBDs serve as the energy source to produce hydrolyzed ATP, while the MSDs provide support for drug binding, ABCC1 Confers Resistance to Betulin putative drug transport channel, dimerization, and trafficking [4]. MRP1 has a wide distribution, for example throughout the adrenal gland, bladder, choroid plexus, helper T cells, and muscle cells [8]

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