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Metal- and metalloid-based compounds to target and reverse cancer multidrug resistance
Drug Resistance Updates ( IF 15.8 ) Pub Date : 2021-08-06 , DOI: 10.1016/j.drup.2021.100778
Andreia Valente 1 , Ana Podolski-Renić 2 , Isabella Poetsch 3 , Nenad Filipović 4 , Óscar López 5 , Iztok Turel 6 , Petra Heffeter 3
Affiliation  

Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.



中文翻译:

靶向和逆转癌症多药耐药性的金属和准金属化合物

耐药性仍然是癌症治疗失败的主要原因,尤其是在疾病的晚期。然而,基于其多功能化学,金属和准金属化合物提供了设计微调药物以规避甚至专门针对耐药癌细胞的可能性。基于铂类药物在临床中的重要性,存在两个主要的耐药性逆转策略:克服对铂类药物的耐药性以及基于 ABC 外排泵的多药耐药性。目前的综述概述了药物设计的两个方面,并讨论了该领域的未解决问题。本文涵盖的耐药性领域包括:1) 参与金属摄取、流出或细胞内分布的蛋白质表达改变,2) 通过 ABC 转运蛋白增强药物流出,3) 耐药癌细胞的代谢改变,4) 硫醇或氧化还原稳态改变,5) DNA 损伤识别和 DNA 损伤修复增强,6) 细胞凋亡诱导受损和 7) 与免疫系统的相互作用改变。这篇综述代表了第一个金属(包括铂、钌、铱、金和铜)和准金属药物(例如砷和硒)的集合,这些药物显示出抗药性逆转活性。特别关注以过表达 ABC 转运蛋白的癌细胞的附带敏感性为特征的化合物。通过这种方法,我们希望引起对该领域开放研究问题的关注。有必要进行未来的研究,以更深入地了解针对特定耐药性模式的最有效化合物的作用机制。

更新日期:2021-08-15
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