MD, PhD, Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
J Clin Endocrinol Metab. 2013 Sep;98(9):E1465-73. doi: 10.1210/jc.2013-1364. Epub 2013 Aug 22.
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.
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.
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 (i.p.).
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).
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.
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具有一定的合理性。舒尼替尼对间变性甲状腺癌（ATC）显示出有前景的初步疗效，并且已被用于一些不符合临床试验条件的患者。
本研究旨在研究舒尼替尼对 ATC 和微血管内皮细胞的体外和体内活性，以及观察到的舒尼替尼活性的分子机制。
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（8305C 和 FB3）进行增殖和凋亡测定。通过 ELISA 和 Western blot 定量测定血管内皮生长因子受体-2、表皮生长因子受体、ERK1/2 和 Akt 磷酸化。通过实时 PCR 评估 cyclin-D1 mRNA 表达，通过 ELISA 测量 cyclin-D1 细胞内浓度。在裸鼠 8305C 肿瘤异种移植模型中，以 50mg/kg/d（腹腔内）给予舒尼替尼。
舒尼替尼对内皮细胞和 ATC 细胞均具有抗增殖和促凋亡活性。在激活的内皮细胞中，舒尼替尼治疗后磷酸化血管内皮生长因子受体-2 水平显著降低。舒尼替尼治疗显著抑制内皮细胞和癌细胞中磷酸化表皮生长因子受体、ERK1/2 和 Akt 的磷酸化，并抑制 cyclin-D1 mRNA 和蛋白表达。体内给予舒尼替尼可显著抑制肿瘤生长（P<0.05）。
舒尼替尼通过抑制 Akt 和 ERK1/2 磷酸化以及下调 cyclin-D1，对激活的内皮细胞和 ATC 细胞具有体内外活性。
