Lin Han, Jiang Xian, Zhu Huaqiang, Jiang Wenjing, Dong Xuesong, Qiao Haiquan, Sun Xueying, Jiang Hongchi
Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
Department of General Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Tumour Biol. 2016 Jan;37(1):381-91. doi: 10.1007/s13277-015-3816-1. Epub 2015 Jul 29.
Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte growth factor (HGF) receptor), and other receptor tyrosine kinases. Cabozantinib has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain and dose-dependent adverse events are very common. The present study has demonstrated that 2-methoxyestradiol (2ME2), an inhibitor of hypoxia-inducible factors (HIFs) and a promising anticancer agent under investigation in clinical trials, strengthens anticancer activities of cabozantinib against MTC cells in vitro and in vivo. The activated hypoxia-inducible pathways, which are mainly regulated by HIF-1, contribute to the resistance of hypoxic MTC cells to cabozantinib. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. Administration of 2ME2 enhanced the efficacy of cabozantinib in suppressing the growth of MTC cell line xenografts and patient-derived xenografts established in mice. Given that 2ME2 targets insensitive hypoxic cancer cells to cabozantinib and can inhibit the activated pathways by cabozantinib, the present results warrant further investigation of 2ME2, particularly in combination with cabozantinib, for the treatment of MTC.
卡博替尼是一种多靶点酪氨酸激酶抑制剂，可靶向血管内皮生长因子（VEGF）受体（VEGFR）-2、MET（c-Met，也称为肝细胞生长因子（HGF）受体）以及其他受体酪氨酸激酶。卡博替尼最近已被批准用于治疗晚期甲状腺髓样癌（MTC），但其长期益处仍不确定，且剂量依赖性不良事件非常常见。本研究表明，2-甲氧基雌二醇（2ME2）是一种缺氧诱导因子（HIFs）抑制剂，也是一种正在临床试验中研究的有前景的抗癌药物，可增强卡博替尼在体外和体内对MTC细胞的抗癌活性。主要由HIF-1调节的激活的缺氧诱导途径导致缺氧MTC细胞对卡博替尼产生抗性。卡博替尼在翻译水平上调HIF-1α表达，并增加包括VEGF、乳酸脱氢酶A（LDHA）、HGF和MET在内的下游因子的表达。2ME2通过下调缺氧MTC细胞中HIF-1α的表达并抑制其核转位，纠正了卡博替尼激活的途径。给予2ME2可增强卡博替尼抑制在小鼠中建立的MTC细胞系异种移植物和患者来源异种移植物生长的功效。鉴于2ME2可靶向对卡博替尼不敏感的缺氧癌细胞，并可抑制卡博替尼激活的途径，本研究结果值得进一步研究2ME2，特别是与卡博替尼联合使用，用于治疗MTC。
