Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
Toxicol Lett. 2019 Oct 15;315:1-8. doi: 10.1016/j.toxlet.2019.08.009. Epub 2019 Aug 14.
Arsenic trioxide (AsO) has been used clinically for the treatment of acute promyelocytic leukemia and some solid tumors. However, the mechanisms of its anti-tumor effects are still elusive. Angiogenesis is a key process for tumor initiation, and increasing evidence has supported the role of anti-angiogenesis caused by arsenic in tumor suppression, although the detailed mechanism is not well understood. In the present study, we found that AsO significantly inhibited the angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and this was mediated by the upregulation of FoxO3a. Knockdown of FoxO3a could restore the angiogenic ability of HUVECs. Moreover, vascular endothelial cell-specific knockout of FoxO3a in mice could disrupt the anti-angiogenesis effect of AsO and endow the tumors with resistance to AsO treatments. Our results revealed a new mechanism by which AsO suppresses angiogenesis and tumor growth.
三氧化二砷（As2O3）已被临床用于治疗急性早幼粒细胞白血病和一些实体瘤。然而，其抗肿瘤作用的机制仍难以捉摸。血管生成是肿瘤发生的关键过程，越来越多的证据支持砷引起的抗血管生成在肿瘤抑制中的作用，尽管其详细机制尚不清楚。在本研究中，我们发现 As2O3 可显著抑制人脐静脉内皮细胞（HUVEC）的体外血管生成，这是通过 FoxO3a 的上调介导的。FoxO3a 的敲低可以恢复 HUVEC 的血管生成能力。此外，小鼠血管内皮细胞特异性 FoxO3a 敲除可破坏 As2O3 的抗血管生成作用，并使肿瘤对 As2O3 治疗产生耐药性。我们的结果揭示了 As2O3 抑制血管生成和肿瘤生长的新机制。
