Kimura Takayuki, Uesugi Mai, Takase Kazuma, Miyamoto Norimasa, Sawada Kohei
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan; Department of Genomics-Based Drug Discovery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Toxicol Appl Pharmacol. 2017 Aug 15;329:282-292. doi: 10.1016/j.taap.2017.06.015. Epub 2017 Jun 15.
Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes. First, we found that treatment with geldanamycin or other Hsp90 inhibitors (tanespimycin, ganetespib, or BIIB021) significantly attenuated sunitinib-induced cytotoxicity in rat H9c2 cardiomyocytes, suggesting a drug-class effect of Hsp90 inhibitors. We then examined the mechanisms underlying sunitinib-induced cytotoxicity and found that sunitinib induced autophagy in H9c2 cells and that pretreatment with geldanamycin inhibited the induction of autophagy by promoting degradation of the autophagy-related proteins Atg7, Beclin-1, and ULK1. Pharmacological assessment with autophagy inhibitors confirmed that geldanamycin attenuated the cytotoxicity of sunitinib by interfering with autophagy. In addition, we found that the molecular chaperone Hsp70, which is induced by geldanamycin, was not involved in the attenuation of sunitinib-induced cytotoxicity. Finally, to provide more clinically relevant data, we confirmed that geldanamycin attenuated sunitinib-induced cytotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Together, these data suggest that geldanamycin attenuates sunitinib-induced cytotoxicity in cardiomyocytes by inhibiting the autophagy pathway. Thus, the further investigation of combination or sequential treatment with an Hsp90 inhibitor and sunitinib is warranted as a potential strategy of attenuating the cardiotoxicity associated with sunitinib administration in the clinical setting.
苹果酸舒尼替尼（舒尼替尼）是一种口服有效的多靶点酪氨酸激酶抑制剂，具有抗肿瘤和抗血管生成活性。尽管舒尼替尼对治疗胃肠道间质瘤、晚期肾细胞癌或胰腺神经内分泌肿瘤患者有效，但已有与舒尼替尼给药相关的不良心脏事件的报道。在此，我们研究了热休克蛋白（Hsp）90抑制剂格尔德霉素对舒尼替尼诱导的心肌细胞毒性的影响。首先，我们发现用格尔德霉素或其他Hsp90抑制剂（坦螺旋霉素、ganetespib或BIIB021）处理可显著减轻舒尼替尼诱导的大鼠H9c2心肌细胞毒性，提示Hsp90抑制剂具有类药物效应。然后，我们研究了舒尼替尼诱导细胞毒性的潜在机制，发现舒尼替尼在H9c2细胞中诱导自噬，而用格尔德霉素预处理可通过促进自噬相关蛋白Atg7、Beclin-1和ULK1的降解来抑制自噬的诱导。用自噬抑制剂进行的药理学评估证实，格尔德霉素通过干扰自噬减轻了舒尼替尼的细胞毒性。此外，我们发现由格尔德霉素诱导的分子伴侣Hsp70与舒尼替尼诱导的细胞毒性减轻无关。最后，为了提供更多临床相关数据，我们证实格尔德霉素可减轻舒尼替尼对人诱导多能干细胞衍生心肌细胞的细胞毒性。总之，这些数据表明格尔德霉素通过抑制自噬途径减轻了舒尼替尼诱导的心肌细胞毒性。因此，作为在临床环境中减轻与舒尼替尼给药相关的心脏毒性的潜在策略，对Hsp90抑制剂与舒尼替尼联合或序贯治疗进行进一步研究是有必要的。
