多药耐药性相关蛋白1的过表达可通过增加多柔比星从心肌细胞的外流来防止心脏毒性。

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-03-14 DOI:10.1002/jgm.3681
Cindy Y. Kok, Sindhu Igoor, Renuka Rao, Shinya Tsurusaki, Tracy Titus, Lauren M. MacLean, Megha Kadian, Rhys Skelton, James J. H. Chong, Eddy Kizana
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引用次数: 0

摘要

多柔比星是一种常用的抗癌药物,可用于治疗多种恶性肿瘤。然而,其主要不良反应是心脏毒性,这种毒性与剂量有关,可以是急性的,也可以是慢性的。多柔比星通过 DNA 损伤、自由活性氧自由基的形成和诱导细胞凋亡造成伤害。我们的目的是在人类 iPS 细胞(hiPSC-CM)衍生的心肌细胞中诱导多药耐药性相关蛋白 1(MRP1)的表达,以确定这是否能使细胞有效清除多柔比星并提供心脏保护。我们生成了编码 MRP1 的慢病毒载体(LV.MRP1),并通过定量 PCR 和 Western 印迹分析验证了它在 HEK293T 细胞和干细胞衍生心肌细胞(hiPSC-CM)中的功能。我们还通过量化转运体从细胞中输出的荧光染料量,测试了过表达 MRP1 的活性。我们证明过表达 MRP1 的细胞中染料螯合减少。最后,我们证明了转导了 LV.MRP1 的 hiPSC-CM 可防止多柔比星损伤。总之,我们已经证明,我们可以成功地在 hiPSC-CM 中过表达 MRP1 蛋白,其功能性转运体活性可保护细胞免受多柔比星诱导的毒性损伤。
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Overexpression of multidrug resistance-associated protein 1 protects against cardiotoxicity by augmenting the doxorubicin efflux from cardiomyocytes

Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.

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