Brandão Sofia Reis, Carvalho Félix, Amado Francisco, Ferreira Rita, Costa Vera Marisa
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira n° 28, 4050-313 Porto, Portugal; LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira n° 28, 4050-313 Porto, Portugal.
Metabolism. 2022 Sep;134:155250. doi: 10.1016/j.metabol.2022.155250. Epub 2022 Jul 6.
Several anticancer agents have been associated with cardiac toxic effects. The currently proposed mechanisms to explain cardiotoxicity differ among anticancer agents, but in fact, the specific modulation is not completely elucidated. Thus, this systematic review aims to provide an integrative perspective of the molecular mechanisms underlying the toxicity of anticancer agents on heart muscle while using a high-throughput technology, mass spectrometry (MS)-based proteomics. A literature search using PubMed database led to the selection of 27 studies, of which 13 reported results exclusively on animal models, 13 on cardiomyocyte-derived cell lines and only one included both animal and a cardiomyocyte line. The reported anticancer agents were the proteasome inhibitor carfilzomib, the anthracyclines daunorubicin, doxorubicin, epirubicin and idarubicin, the antimicrotubule agent docetaxel, the alkylating agent melphalan, the anthracenedione mitoxantrone, the tyrosine kinase inhibitors (TKIs) erlotinib, lapatinib, sorafenib and sunitinib, and the monoclonal antibody trastuzumab. Regarding the MS-based proteomic approaches, electrophoretic separation using two-dimensional (2D) gels coupled with tandem MS (MS/MS) and liquid chromatography-MS/MS (LC-MS/MS) were the most common. Overall, the studies highlighted 1826 differentially expressed proteins across 116 biological processes. Most of them were grouped in larger processes and critically analyzed in the present review. The selection of studies using proteomics on heart muscle allowed to obtain information about the anticancer therapy-induced modulation of numerous proteins in this tissue and to establish connections that have been disregarded in other studies. This systematic review provides interesting points for a comprehensive understanding of the cellular cardiotoxicity mechanisms of different anticancer drugs.
几种抗癌药物已被证实与心脏毒性作用有关。目前提出的解释心脏毒性的机制在不同抗癌药物之间存在差异，但实际上，具体的调节机制尚未完全阐明。因此，本系统综述旨在利用基于质谱（MS）的蛋白质组学这一高通量技术，提供抗癌药物对心肌毒性潜在分子机制的综合观点。使用PubMed数据库进行文献检索后筛选出27项研究，其中13项仅报告了动物模型的结果，13项关于心肌细胞衍生细胞系，只有1项同时包括动物和心肌细胞系。所报道的抗癌药物有蛋白酶体抑制剂卡非佐米、蒽环类药物柔红霉素、阿霉素、表柔比星和伊达比星、抗微管药物多西他赛、烷化剂美法仑、蒽二酮米托蒽醌、酪氨酸激酶抑制剂（TKIs）厄洛替尼、拉帕替尼、索拉非尼和舒尼替尼，以及单克隆抗体曲妥珠单抗。关于基于MS的蛋白质组学方法，使用二维（2D）凝胶结合串联MS（MS/MS）和液相色谱 - MS/MS（LC - MS/MS）的电泳分离是最常见的。总体而言，这些研究突出了116个生物学过程中的1826种差异表达蛋白质。其中大多数被归为更大的过程，并在本综述中进行了批判性分析。对心肌进行蛋白质组学研究的选择使得能够获得关于抗癌治疗引起的该组织中众多蛋白质调节的信息，并建立在其他研究中被忽视的联系。本系统综述为全面理解不同抗癌药物的细胞心脏毒性机制提供了有趣的观点。
