Chen Xuan-Yu, Yang Yuqi, Wang Jing-Quan, Wu Zhuo-Xun, Li Jing, Chen Zhe-Sheng
College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang, China.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.
Front Oncol. 2021 Feb 25;11:640656. doi: 10.3389/fonc.2021.640656. eCollection 2021.
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.
桦木醇是一种羽扇豆烷型五环三萜，从白桦树皮中分离得到。它具有广泛的生物学和药理学特性，如抗炎、抗肿瘤、抗病毒和抗菌活性。在此，我们探讨了可能导致桦木醇耐药的因素，特别是其与ATP结合盒亚家族C成员1（ABCC1）的相互作用。ABCC1是ATP结合盒（ABC）转运蛋白家族的重要成员，在介导天然来源抗癌药物的多药耐药（MDR）中起核心作用。基于MTT的细胞活力测定表明，ABCC1过表达能够使癌细胞系和基因转染细胞系对桦木醇脱敏，并且这种桦木醇诱导的耐药性可被25μM的已知ABCC1抑制剂MK571拮抗。此外，桦木醇以浓度依赖性和时间依赖性方式上调ABCC1蛋白表达水平，还阻断ABCC1介导的转运功能。随后，在计算对接分析中获得了桦木醇的高亲和力评分，表明桦木醇与ABCC1有强烈相互作用。
