Abstract

Celastrol, a Chinese herbal medicine, has already shown an inhibition effect on retinoblastoma growth activity in our previous research, but its mechanism is not well understood. Angiogenesis is a main driving force in many tumors. Here, we studied whether celastrol could inhibit angiogenesis-mediated retinoblastoma growth, if so, through what mechanism. In this work, we developed celastrol-loaded polymeric nanomicelles to improve the poor water solubility of celastrol. When given an intraperitoneal injection to mice bearing human retinoblastoma xenografts, celastrol nanomicelles (CNMs, 27.2 mg/kg/2 days) significantly reduced the weight and the volume of tumors and decreased tumor angiogenesis. We found that CNMs suppressed hypoxia-induced proliferation, migration, and invasion by human umbilical vascular endothelial cells (EA.hy 926) in a dose-dependent manner. Furthermore, CNMs inhibited SO-Rb 50 cells-induced sprouting of the vessels and vascular formation in chick embryo chorioallantoic membrane assay in vitro. To understand the molecular mechanism of these activities, we assessed the signaling pathways in CoCl₂ treated EA.hy 926. CNMs inhibited the hypoxia-induced HIF-1α and VEGF. In conclusion, our results reveal that CNMs target the HIF-1α/VEGF pathway, which may be an important reason for the suppression of retinoblastoma growth and angiogenesis.

摘要

在我们之前的研究中，中草药Celastrol已显示出对成视网膜细胞瘤生长活性的抑制作用，但其机理尚不清楚。血管生成是许多肿瘤的主要驱动力。在这里，我们研究了Celastrol是否可以通过什么机制抑制血管生成介导的视网膜母细胞瘤的生长。在这项工作中，我们开发了负载Celastrol的聚合物纳米胶束，以改善Celastrol的不良水溶性。当对携带人成视网膜细胞瘤异种移植物的小鼠进行腹膜内注射时，Celastrol纳米胶束（CNMs，27.2 mg / kg / 2天）显着降低了肿瘤的重量和体积，并减少了肿瘤血管生成。我们发现CNM抑制了缺氧诱导的人脐带血管内皮细胞（EA。hy 926）的剂量依赖性。此外，在鸡胚绒膜尿囊膜测定中，CNMs抑制了SO-Rb 50细胞诱导的血管萌发和血管形成体外。为了了解这些活性的分子机制，我们评估了CoCl ₂处理的EA.hy 926中的信号传导途径。CNMs抑制缺氧诱导的HIF-1α和VEGF。总之，我们的结果表明CNM靶向HIF-1α/ VEGF途径，这可能是抑制视网膜母细胞瘤生长和血管生成的重要原因。