舒尼替尼常见不良反应的分子机制

Molecular mechanisms of sunitinib-associated side effects

舒尼替尼是一种靶向多种受体酪氨酸激酶（RTK）抑制剂，用于治疗晚期肾细胞癌、伊马替尼不耐受和伊马替尼耐药的难治性胃肠道间质瘤。舒尼替尼常见的不良反应包括疲劳与乏力，皮肤黏膜不良反应（手足皮肤反应、皮肤颜色改变、头发色素脱失、甲下线状出血、口腔炎、脱发等），心血管不良反应（高血压、有/无症状的左心室射血分数下降、心功能衰竭等），以及甲状腺功能减退等。舒尼替尼致疲劳与乏力的机制可能与其抑制一磷酸腺苷依赖的蛋白激酶、诱发缺氧和影响葡萄糖转运及降低摄取葡萄糖的能力有关。舒尼替尼致皮肤黏膜不良反应的机制可能与其抑制血管内皮生长因子和血小板衍生生长因子、阻断黑素细胞小眼畸形相关转录因子的激活、抑制信号传导与转录激活因子3、促进Fas/FasL表达及诱发线粒体损伤有关。舒尼替尼致心血管不良反应的机制可能与其对心脏血小板衍生生长因子脱靶效应并抑制心脏血管生成、抑制核糖体蛋白S6激酶和一磷酸腺苷依赖性蛋白激酶、诱发线粒体损伤及抑制一氧化氮生成有关。舒尼替尼致甲状腺功能减退的机制可能与其抗血管生成致甲状腺血供减少以及抑制甲状腺过氧化物酶活性有关。

Sunitinib is one of the targeting multiple receptor tyrosine kinase inhibitors. Sunitinib is used to treat advanced renal cell carcinoma, and refractory gastrointestinal stromal tumor patients with which are intolerant or resistant to imatinib. The common adverse reactions of sunitinib include fatigue and weakness, mucocutaneous adverse reactions （hand foot skin reaction, changing in skin color, hair depigmentation, splinter hemorrhages, stomatitis, and lipsotrichia）, adverse reactions in cardiovascular system （hypertension, left ventricular ejection fraction decrease with or without symptoms, heart failure）, and hypothyroidism etc. The mechanism of fatigue and weakness may be related to the inhibition of adenosine monophosphate-activated protein kinase, inducing hypoxia, influence of glucose transport, and decreased capability of glucose uptake. The mechanism of adverse reactions in mucocutaneous tissues may be related to the inhibition of vascular endothelial growth factor and platelet-derived growth factor, blocking the activation of melanocyte microphthalmia associated transcription factor, inhibition of signal transduction and activators of transcription 3, promoting the expression of Fas/Fas L, and inducing the mitochondrial injury. The mechanism of adverse reactions in cardiovascular system may be related to the off-target effects to heart platelet-derived growth factor receptor and the inhibition of heart angiogenesis, the inhibition of ribosomal protein S6 kinase and AMP dependent protein kinase, inducing the mitochondrial injury, and he inhibition of nitric oxide production. The mechanism of hypothyroidism due to sunitinib may be related to the decrease of the blood supply of thyroid and inhibition of the activity of thyroid peroxidase induced by antiangiogenesis of sunitinib.