Drug Safety Research and Evaluation, Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
BMC Pharmacol Toxicol. 2021 Oct 6;22(1):55. doi: 10.1186/s40360-021-00527-5.
Sunitinib is known to cause cardiotoxicity in clinical settings. However, among sunitinib-treated patients experiencing adverse cardiac events, decreased cardiac function was reportedly reversible in > 50% of the patients. We previously showed that anti-cancer drugs such as sunitinib cause marked sarcomere disruption in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and the extent of sarcomere disruption can be used to predict drug-induced cardiotoxicity in humans. The aim of this study is to investigate whether the reversibility of sunitinib-induced cardiac events in clinical settings can be mimicked in vitro, and to examine the molecular mechanism responsible for sunitinib-induced cardiotoxicity focusing on the Hippo pathway.
iPSC-CMs were stimulated with sunitinib for 72 h and the morphology of sarcomere structures were analyzed by high-content analysis before and after sunitinib washout. To examine the involvement of the Hippo pathway in the sunitinib-induced sarcomere disruption, the extent of nuclear localization of YAP1 (yes-associated protein 1, a Hippo signaling target) was determined. iPSC-CMs were also stimulated with sunitinib and a small molecule inhibitor of the Hippo pathway, XMU-MP-1 and sarcomere structures were analyzed.
We observed a spontaneous recovery in cardiac sarcomeres in iPSC-CMs that were significantly disrupted by sunitinib treatment after a 72 h or 144 h washout of sunitinib. The extent of nuclear localization of YAP1 was significantly reduced after sunitinib stimulation and tended to return to normal levels after drug washout. Simultaneous stimulation of iPSC-CM with sunitinib and XMU-MP-1 suppressed the sunitinib-induced disruption of sarcomeres.
These results indicate that iPSC-CMs have the ability to recover from sunitinib-induced sarcomere disruption, and the Hippo pathway plays a role in the process of sunitinib-induced disruption of sarcomere and its recovery. Inhibition of the Hippo pathway may help to develop a co-medication strategy for mitigating the risk of sunitinib-induced adverse cardiac events.
在临床环境中，已知舒尼替尼会引起心脏毒性。然而，在接受舒尼替尼治疗且发生不良心脏事件的患者中，>50%的患者报告称心脏功能下降是可逆的。我们之前表明，舒尼替尼等抗癌药物会导致人诱导多能干细胞衍生的心肌细胞（iPSC-CMs）中的肌节严重破坏，并且肌节破坏的程度可以用于预测人类的药物引起的心脏毒性。本研究的目的是研究在临床环境中舒尼替尼引起的心脏事件的可逆性是否可以在体外模拟，并检查导致舒尼替尼心脏毒性的分子机制，重点是 Hippo 通路。
用舒尼替尼刺激 iPSC-CMs72 小时，并用高内涵分析在舒尼替尼洗脱前后分析肌节结构的形态。为了研究 Hippo 通路在舒尼替尼引起的肌节破坏中的作用，确定 YAP1（yes-associated protein 1，Hippo 信号靶标）的核定位程度。还刺激 iPSC-CMs 用舒尼替尼和 Hippo 通路的小分子抑制剂 XMU-MP-1 进行刺激，并分析肌节结构。
我们观察到在 iPSC-CMs 中，在经过 72 小时或 144 小时的舒尼替尼洗脱后，心肌肌节在被舒尼替尼显著破坏后自发恢复。在用舒尼替尼刺激后，YAP1 的核定位程度显著降低，并且在药物洗脱后趋于恢复正常水平。同时刺激 iPSC-CM 用舒尼替尼和 XMU-MP-1 抑制了舒尼替尼引起的肌节破坏。
这些结果表明，iPSC-CMs 具有从舒尼替尼引起的肌节破坏中恢复的能力，Hippo 通路在舒尼替尼引起的肌节破坏及其恢复过程中起作用。抑制 Hippo 通路可能有助于开发联合用药策略来降低舒尼替尼引起的不良心脏事件的风险。
