Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway

Angiogenesis plays a crucial role in tumor growth and metastases. The extent of angiogenesis correlates with the increased invasion and metastasis in a variety of human neoplasms. Vascular endothelial cell proliferation and migration are critical steps in angiogenesis and are regulated by various growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The topoisomerase I inhibitor topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin) is a water-soluble camptothecin analogue and possesses an indirect in vivo antitumor effect mediated through the inhibition of angiogenesis. We found that topotecan inhibited VEGF- and bFGF-induced migration of human umbilical vein endothelial cells (HUVECs) in vitro. The migration of HUVECs was also inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. Thus, we investigated the possibility that topotecan's antiangiogenic property might be mediated by its inhibitory effect on VEGF- and bFGF-induced activation of the PI3K-Akt signaling pathway. We found that topotecan treatment decreased the amount of the phosphorylated (activated) form of Akt, but not the amount of Akt protein, in HUVECs. Moreover, transient transfection of constitutive active akt cDNA into HUVECs reversed the topotecan-mediated decrease in HUVEC migration. These results suggest that the antiangiogenic activity of topotecan is mediated in part by downregulating the PI3K-Akt signaling pathway. (C) 2002 Wiley-Liss, Inc.