Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase.
Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase.
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DOI：
10.1111/j.1752-8062.2008.00090.x
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Force T
中科院分区：
文献类型：
--
作者：
Kerkela R;Woulfe KC;Durand JB;Vagnozzi R;Kramer D;Chu TF;Beahm C;Chen MH;Force T
酪氨酸激酶抑制剂(TKIs)正在改变恶性肿瘤患者的治疗方式。一种这样的药物，舒尼替尼(舒坦，辉瑞)，已经显示出对各种实体肿瘤的活性。舒尼替尼是“多靶点”的，抑制生长因子受体，调节肿瘤血管生成和肿瘤细胞存活。然而，心脏功能障碍一直与它的使用有关。确定与舒尼替尼相关的心功能障碍的靶点可以指导未来的药物设计，在保持抗癌活性的同时降低毒性。在此，我们发现舒尼替尼诱导的心力衰竭患者心脏存在严重的线粒体结构异常。在培养的心肌细胞中，舒尼替尼导致线粒体膜电位的丧失和能量的下降。尽管有后者，但在用舒尼替尼处理的小鼠心脏和培养的心肌细胞中，AMPK活性降低，这是由于舒尼替尼对AMPK的直接抑制，在能量妥协的情况下，AMPK活性应该增加。关键的是，我们发现腺病毒介导的AMPK活性突变体的基因转移减少了舒尼替尼诱导的细胞死亡。我们的研究结果表明，AMPK抑制在舒尼替尼心肌细胞毒性中起核心作用，这突出了TKI的非靶点效应可能导致心脏毒性。虽然多靶点可以增强肿瘤细胞的杀伤力，但这必须与心功能不全的潜在风险增加相平衡。
Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer), has demonstrated activity against a variety of solid tumors. Sunitinib is “multi-targeted,” inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However cardiac dysfunction has been associated with its use. Identification of the target of sunitinib associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anti-cancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib-induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, AMPK activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib-treated mice and cardiomyocytes in culture and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus-mediated gene transfer of an actived mutant of AMPK reduces sunitinib-induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off-target effects of TKIs contributing to cardiotoxicity. While multi-targeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.
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