Effects of Cholesterol on the Breast Cancer Resistance Protein: Studies through the Synthesis and Biological Evaluation of Chemical Tools.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-01-21 DOI:10.1002/cmdc.202400712

Ahcène Boumendjel, Ingrid Fatima Zattoni, Bruna Estelita Rugisnk, Isadora da Silva Zanzarini, Alan Guilherme Gonçalves, Vivian Rotuno Moure, Glaucio Valdameri

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Abstract

The breast cancer resistance protein (BCRP/ABCG2) plays a major role in the multidrug resistance of cancers toward chemotherapeutic treatments. It was demonstrated that cholesterol regulates the ABCG2 activity, suggesting that lower levels of membrane cholesterol decrease the ABCG2 activity in mammalian cells. However, the precise mechanism remains unclear. To better understand the role of cholesterol in the ABCG2 activity, we studied the ABCG2-mediated efflux of different substrates in the presence of different concentrations of cholesterol. Moreover, we synthetized derivatives of cholesterol linked either to known ABCG2 inhibitors or fluorescents probes. A chalcone-cholesterol was synthetized to investigate the influence of cholesterol on ABCG2 inhibition, and a BODIPY-cholesterol was developed to track cholesterol trafficking on mammalian cells and investigate the behavior of cholesterol as an ABCG2 substrate. The obtained results with three different substrates of ABCG2 showed that cholesterol did not affect the intracellular amount of substrates nor the transport activity.

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胆固醇对乳腺癌抵抗蛋白的影响：化学工具的合成及生物学评价研究

乳腺癌耐药蛋白（BCRP/ABCG2）在癌症对化疗的多药耐药中起着重要作用。结果表明，胆固醇可调节ABCG2活性，表明低水平的膜胆固醇可降低哺乳动物细胞中ABCG2活性。然而，确切的机制尚不清楚。为了更好地了解胆固醇在ABCG2活性中的作用，我们研究了不同浓度胆固醇存在下不同底物介导的ABCG2外排。此外，我们还合成了与已知ABCG2抑制剂或荧光探针相连的胆固醇衍生物。研究人员合成了一种查尔酮-胆固醇来研究胆固醇对ABCG2抑制的影响，并开发了一种bodippy -胆固醇来跟踪胆固醇在哺乳动物细胞上的转运，并研究胆固醇作为ABCG2底物的行为。三种不同底物ABCG2的实验结果表明，胆固醇不影响细胞内底物的量，也不影响转运活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.