The growth and metastasis of tumors depend on angiogenesis. Tumor angiogenesis is initiated by the secretion of growth factors from tumor cells; downstream signals are then triggered in pre-existing blood vessels to sprout a new vascular network. Trichosanthin (TCS) is a type I ribosome-inactivating protein that has anti-tumor activity, but the underlying mechanism remains unclear. In this study, we found that a non-toxic dose of TCS decreased the wound-healing and the migration of H5V mouse heart capillary endothelial cells (ECs) induced by human choriocarcinoma (JAR) cells, as well as the JAR-induced angiogenesis of rat third-order mesenteric arteries. TCS was effective on both tumor cells and ECs/arteries. First, TCS decreased vascular endothelial growth factor transcription and secretion by JAR cells. Second, TCS consequently inhibited the tumor cell-induced, extracellular signal-regulated kinase-mediated angiogenic signal in ECs and blood vessels. In conclusion, the ability of TCS to inhibit tumor angiogenesis contributes to its anti-tumor activity. (C) 2012 Elsevier Inc. All rights reserved.