Yuan Wenshuang, Su Chang, Yang Xiaotong, Li Yueqi, Cao Yiou, Liang Xin, Liu Jianwen
Department of Surgery, Minhang Hospital, Fudan University, Shanghai, People's Republic of China.
State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China.
J Cell Biochem. 2019 Oct;120(10):16978-16989. doi: 10.1002/jcb.28959. Epub 2019 May 20.
The effects of ethoxy-erianin phosphate (EBTP) on cell proliferation, mitotic cell arrest, migration, infiltration, and endothelial tubular structures were evaluated in this study. The antiproliferative activity of EBTP and combretastatin A-4P (CA4P) was analyzed on several tumor cells (including MCF-7, HeLa, 2LL, and 2LL-IDO) and on an endothelial cell (human umbilical vein endothelial cells [HUVECs]) as well as a human normal liver cell (L02). The results showed that EBTP possessed antiproliferative activity in the micromole range and was relatively less toxic than CA4P. Treating HUVECs with EBTP caused cell accumulation in the G2/M phase, and wound-healing assays indicated that EBTP inhibited cell migration. Furthermore, EBTP and CA4P destroyed the vasculature in endothelial cells and showed vascular disrupting activity of the chorioallantoic membrane in fertilized chicken eggs. In addition, we found that EBTP suppressed the expression of indoleamine 2,3-dioxygenase (IDO) and significantly inhibited IDO-induced migration and infiltration of 2LL-IDO cells. Administration of EBTP blocked vasculogenic mimicry in 2LL-IDO cells, which was typically observed in tube formation assays of 2LL-IDO cells. Moreover, the results of Lewis lung carcinoma in mice showed a high inhibition rate of EBTP. EBTP is an effective vascular disrupting agent that is superior to CA4P and may prevent and treat malignancy by inhibiting the expression of IDO.
本研究评估了磷酸乙氧基毛兰素（EBTP）对细胞增殖、有丝分裂细胞阻滞、迁移、浸润及内皮管状结构的影响。分析了EBTP和康普瑞他汀A-4P（CA4P）对几种肿瘤细胞（包括MCF-7、HeLa、2LL和2LL-IDO）、一种内皮细胞（人脐静脉内皮细胞[HUVECs]）以及一种人正常肝细胞（L02）的抗增殖活性。结果表明，EBTP在微摩尔范围内具有抗增殖活性，且毒性比CA4P相对较小。用EBTP处理HUVECs导致细胞在G2/M期积累，伤口愈合试验表明EBTP抑制细胞迁移。此外，EBTP和CA4P破坏了内皮细胞中的脉管系统，并在受精鸡蛋的尿囊膜上显示出血管破坏活性。另外，我们发现EBTP抑制吲哚胺2,3-双加氧酶（IDO）的表达，并显著抑制IDO诱导的2LL-IDO细胞的迁移和浸润。给予EBTP可阻断2LL-IDO细胞中的血管生成拟态，这在2LL-IDO细胞的管形成试验中通常可以观察到。此外，小鼠Lewis肺癌的结果显示EBTP具有高抑制率。EBTP是一种优于CA4P的有效血管破坏剂，可能通过抑制IDO的表达来预防和治疗恶性肿瘤。
