Overexpression of ABCC1 Confers Drug Resistance to Betulin

• Main Authors: Xuan-Yu Chen, Yuqi Yang, Jing-Quan Wang, Zhuo-Xun Wu, Jing Li, Zhe-Sheng Chen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-02-01
• Series: Frontiers in Oncology
• Subjects: betulin; ATP-binding cassette sub-family C member 1 (ABCC1); multidrug resistance-associated protein 1 (MRP1); multidrug resistance (MDR); natural product
• Online Access: https://www.frontiersin.org/articles/10.3389/fonc.2021.640656/full

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.