The effect of benzosuberene analogues on endothelial cell morphology and tube formation

Abstract

KGP18 is a tubulin‐binding, benzosuberene‐based small molecule with remarkable cytotoxicity against selected human cancer cell lines (BMC 2008 16, 8161–8171). Its structure together with its ability to inhibit tubulin polymerization into microtubules in vitro suggest that it may act as a vascular disrupting agent (VDA). An adequate blood supply is required for tumor growth and metastasis. VDAs represent a promising new class of anti‐cancer agents that function by selectively disrupting the tumor vasculature, thus starving the tumor of nutrients and oxygen. Tubulin‐binding VDAs inhibit microtubule assembly in the activated endothelial cells, lining the tumor vasculature, leading to cytoskeletal reorganization, increased vascular permeability, cell rounding and detachment, and vessel disruption. The lead benzosuberene analogue (KGP18) and several analogues were assessed for their ability to disrupt microtubules, and cause a rearrangement of F‐actin in human umbilical vein endothelial cells (HUVECs) in cell culture. The disruption of pre‐established tubules formed by HUVECs on Matrigel™ by these benzosuberene analogues was also evaluated. (Supported by Oxigene Inc., the NIH, and CPRIT).