Antiproliferative and Proapoptotic Activity of Sunitinib on Endothelial and Anaplastic Thyroid Cancer Cells via Inhibition of Akt and ERK1/2 Phosphorylation and by Down-Regulation of Cyclin-D1
Antiproliferative and Proapoptotic Activity of Sunitinib on Endothelial and Anaplastic Thyroid Cancer Cells via Inhibition of Akt and ERK1/2 Phosphorylation and by Down-Regulation of Cyclin-D1
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DOI：
10.1210/jc.2013-1364
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发表时间：
2013-09-01
影响因子：
5.8
通讯作者：
Bocci, Guido
中科院分区：
文献类型：
--
作者：
Di Desidero, Teresa;Fioravanti, Anna;Bocci, Guido
背景：最近的实验证据表明使用多靶点酪氨酸激酶抑制剂治疗甲状腺癌的合理性。舒尼替尼在治疗甲状腺未分化癌（ATC）方面显示出有希望的初步结果，并已用于一些不适合临床试验的患者。 目的：本研究的目的是探讨舒尼替尼对 ATC 和微血管内皮细胞的体外和体内活性，以及所观察到的舒尼替尼活性的分子机制。 方法： 增殖和凋亡 在体外暴露于舒尼替尼 72 小时后，对人真皮微血管内皮细胞和 BRAF 或 H-ras 突变的 ATC 细胞（分别为 8305C 和 FB3）进行了测定。通过 ELISA 和 Western blot 对血管内皮生长因子受体 2、上皮生长因子受体、ERK1/2 和 Akt 磷酸化进行定量。通过实时PCR评估Cyclin-D1 mRNA表达，并通过ELISA测量细胞内Cyclin-D1浓度。用舒尼替尼以 50 mg/kg/d (ip) 处理裸鼠的 8305C 肿瘤异种移植物。结果：在内皮细胞和 ATC 细胞中均观察到舒尼替尼的抗增殖和促凋亡活性。舒尼替尼治疗后，活化的内皮细胞中磷酸血管内皮生长因子受体 2 水平显着降低。舒尼替尼治疗内皮细胞和癌细胞中的磷酸表皮生长因子受体、ERK1/2 和 Akt 磷酸化显着受到抑制，细胞周期蛋白 D1 mRNA 和蛋白表达也受到抑制。体内给予舒尼替尼可显着抑制肿瘤生长 (P < .05)。结论：舒尼替尼通过抑制 Akt 和 ERK1/2 磷酸化以及下调细胞周期蛋白-D1，在体外和体内对活化的内皮细胞和 ATC 细胞具有活性。
Context: Recent experimental evidence suggests a rationale for the use of multitarget tyrosine kinase inhibitors for the treatment of thyroid cancers. Sunitinib showed promising preliminary results against anaplastic thyroid cancer (ATC), and it has been used for some patients who are ineligible for clinical trials.Objectives: The aims of this study were to investigate the in vitro and in vivo activity of sunitinib on ATC and on microvascular endothelial cells and the molecular mechanism for the observed sunitinib activity.Methods: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial and on BRAF- or H-ras-mutated ATC cells (8305C and FB3, respectively) after in vitro exposure to sunitinib for 72 hours. Vascular endothelial growth factor receptor-2, epithelial growth factor receptor, ERK1/2, and Akt phosphorylation was quantified by ELISA and Western blot. Cyclin-D1 mRNA expression was evaluated by real-time PCR, and cyclin-D1 intracellular concentrations were measured by ELISA. 8305C tumor xenografts in nude mice were treated with sunitinib at 50 mg/kg/d (ip).Results: Antiproliferative and proapoptotic activity of sunitinib was observed in both endothelial and ATC cells. Phospho-vascular endothelial growth factor receptor-2 levels significantly decreased after sunitinib treatment in activated endothelial cells. Phospho-epidermal growth factor receptor, ERK1/2, and Akt phosphorylation was significantly inhibited by sunitinib treatment in endothelial and cancer cells, and cyclin-D1 mRNA and protein expression was inhibited. Sunitinib administration in vivo caused significant inhibition of tumor growth (P < .05).Conclusions: Sunitinib is active in vitro and in vivo against activated endothelial and ATC cells via the inhibition of Akt and ERK1/2 phosphorylation and through the down-regulation of cyclin-D1.