Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma
Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma
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芳基磺酰胺 64B 抑制缺氧/HIF 诱导的 c-Met 和 CXCR4 表达，并减少葡萄膜黑色素瘤的原发肿瘤生长和转移
DOI：
10.1158/1078-0432.ccr-18-1368
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发表时间：
2019-04-01
影响因子：
11.5
通讯作者：
Van Meir, Erwin G.
中科院分区：
文献类型：
--
作者：
Dong, Lei;You, Shuo;Van Meir, Erwin G.
目的：葡萄膜黑色素瘤（UM）是成人中最常见和最致命的眼内恶性肿瘤。在这里，我们研究了缺氧在UM生长的重要性，并测试了芳基磺酰胺64 B，缺氧诱导因子（HIF）通路的抑制剂在UM动物模型中的抗肿瘤作用，并研究了相关机制。实验设计：将UM细胞植入小鼠眼的葡萄膜中，并用64 B全身治疗小鼠。检查药物对原发性眼肿瘤生长、循环肿瘤细胞、肝转移形成和存活的影响。测定64 B对UM细胞生长、侵袭和缺氧诱导的C-X-C趋化因子受体4（CXCR 4）和间充质-上皮转化因子（c-Met）表达的影响。荧光素酶报告基因测定、染色质免疫沉淀、免疫共沉淀和细胞热位移测定用于确定64 B如何干扰HIF转录复合物。在几种原位小鼠模型中，全身给予64 B对UM具有强效抗肿瘤作用，抑制眼内UM生长（类似于70%减少）和自发性肝转移（类似于50%减少），并延长小鼠存活（P < 0.001），同时耐受良好。64 B抑制缺氧诱导的CXCR 4和c-Met表达，这是肿瘤侵袭和转移的两个关键驱动因素。64 B通过干扰HIF-1 α与p300/CBP辅因子的结合来破坏HIF-1复合物，从而减少p300向MET和CXCR 4基因启动子的募集。结论：64 B化学支架的临床前有效性研究为进一步优化64 B化学支架治疗UM提供了实验依据。
Purpose: Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. ExperimentalDesign: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex.Results: Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (similar to 70% reduction) and spontaneous liver metastasis (similar to 50% reduction), and extending mice survival (P < 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex by interfering with HIF-1 alpha binding to p300/CBP co-factors, thus reducing p300 recruitment to the MET and CXCR4 gene promoters. 64B could thermostabilize p300, supporting direct 64B binding to p300.Conclusions: Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.