Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations.
Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations.
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DOI：
10.1016/j.taap.2011.08.020
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发表时间：
2011-11-15
影响因子：
3.8
通讯作者：
Kolaja KL
中科院分区：
文献类型：
--
作者：
Cohen JD;Babiarz JE;Abrams RM;Guo L;Kameoka S;Chiao E;Taunton J;Kolaja KL
舒尼替尼是一种口服酪氨酸激酶抑制剂，被批准用于治疗晚期肾细胞癌和胃肠道间质瘤，其与临床心脏毒性有关。尽管舒尼替尼心脏毒性的确切机制尚不清楚，但关键的代谢能量调节剂 AMP 激活蛋白激酶 (AMPK) 和核糖体 S 6 激酶 (RSK) 已被假设为致病原因，尽管这是基于啮齿动物模型。为了研究舒尼替尼在人体模型中介导的心脏毒性的机制，研究了具有天然心脏组织的电生理和收缩特性的诱导多能干细胞衍生的心肌细胞（iPSC-CM）。舒尼替尼具有剂量依赖性的心脏毒性，IC50 在低微摩尔范围内，通过细胞 ATP 的损失、氧化型谷胱甘肽的增加以及 iPSC-CM 细胞凋亡的诱导观察到。用 AMPK 激活剂 AICAR 或二甲双胍预处理 iPSC-CM，增加了 pAMPK-T172 和 pACC-S79 的磷酸化，但仅略微减弱了舒尼替尼介导的细胞死亡。此外，其他 AMPK 抑制剂在浓度高达 250 µM 时不会对 iPSC-CM 产生直接细胞毒性。使用高度特异性、不可逆的小分子抑制剂 (RSK-FMK-MEA) 抑制 RSK 不会在低于 250 µM 的 iPSC-CM 中诱导细胞毒性。对舒尼替尼和 RSK-FMK-MEA 介导的传导效应进行了广泛的电生理学分析。综上所述，这些发现表明 AMPK 和 RSK 的抑制并不是舒尼替尼诱导的心脏毒性的主要组成部分。尽管舒尼替尼心脏毒性的确切机制尚不清楚，但很可能是由于同时抑制多种激酶所致。这些数据强调了人类 iPSC-CM 在研究药物引起的心脏毒性潜在分子机制中的效用。
Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC50 in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 µM concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 µM. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity.
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影响因子：
56.9
作者：
Cohen, MS;Zhang, C;Taunton, J
通讯作者：
Taunton, J
DOI：
10.1111/j.1432-1033.1990.tb15293.x
发表时间：
1990-01-12
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DAVIES, SP;SIM, ATR;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
1.3
作者：
Gussak, I;Chaitman, BR;Nerbonne, JM
通讯作者：
Nerbonne, JM
影响因子：
45.3
作者：
Faivre, S;Delbaldo, C;Raymond, E
通讯作者：
Raymond, E
影响因子：
46.9
作者：
Fabian, MA;Biggs, WH;Lockhart, DJ
通讯作者：
Lockhart, DJ