Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).
Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).
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DOI：
10.3389/fphar.2018.00481
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发表时间：
2018
影响因子：
5.6
通讯作者：
Abdel-Aziz H
中科院分区：
文献类型：
--
作者：
Saeed MEM;Mahmoud N;Sugimoto Y;Efferth T;Abdel-Aziz H
白桦酸（BetA）是一种天然存在的五环三萜，从白桦树和许多其他药用植物的外树皮中分离出来。本文研究了白桦酸对耐药肿瘤细胞系的细胞毒活性。p -糖蛋白（MDR1/ABCB1）和BCRP （ABCG2）是已知的介导MDR的atp结合盒（ABC）药物转运体。ABCB5是ABCB1的近亲，ABCB1也介导MDR。EGF受体的组成性激活与化疗耐药的发展密切相关。β抑制P-gp、BCRP、ABCB5和突变激活EGFR过表达细胞，其效果与药物敏感的亲本细胞相似。此外，在美国国家癌症研究所（NCI）的60个细胞系中，ABCB1、BCRP、ABCB5和EGFR的mRNA表达与β的50%抑制浓度（IC50）无关。除了已建立的MDR机制外，我们还试图确定在介导β细胞毒性活性中发挥作用的其他分子机制。出于这个原因，我们对NCI细胞系面板的转录组全微阵列mRNA表达进行了比较和分层聚类分析。多种与β活性显著相关的基因参与不同的生物过程，如细胞周期调节、微管形成、信号转导、转录调节、染色质重塑、细胞粘附、肿瘤抑制、泛素化和蛋白酶体降解。免疫印迹和计算机分析显示，抑制AMFR活性可能是β克服耐多药表型的机制之一。总之，β可能具有治疗难治性肿瘤的潜力。
Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein (MDR1/ABCB1) and BCRP (ABCG2) are known ATP-binding cassette (ABC) drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC50) for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI), USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and in silico analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.
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