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Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression

By G.U. Dachs, A.J. Steele, C. Coralli, C. Kanthou, A.C. Brooks, S.P. Gunningham, M.J. Currie, A.I. Watson, B.A. Robinson and G.M. Tozer

Abstract

Background\ud \ud A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies. Combretastatin A-4 phosphate (CA-4-P) is a tubulin-depolymerising agent in Phase II clinical trials as a vascular disrupting agent. Not much is known of the molecular effect of CA-4-P under tumour conditions. The tumour microenvironment differs markedly from that in normal tissue, specifically with respect to oxygenation (hypoxia). Gene regulation under tumour conditions is governed by hypoxia inducible factor 1 (HIF-1), controlling angiogenic and metastatic pathways.\ud \ud Methods\ud \ud We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.\ud \ud Results\ud \ud CA-4-P treatment under hypoxia tended to reduce HIF-1 accumulation in a concentration-dependent manner, an effect which was more prominent in endothelial cells than in cancer cell lines. Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions in vitro. At these concentrations of CA-4-P under aerobic conditions, nuclear factor κB was activated via the small GTPase RhoA, and expression of the HIF-1 downstream angiogenic effector gene, vascular endothelial growth factor (VEGF-A), was increased.\ud \ud Conclusion\ud \ud Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.\ud \u

Publisher: BioMed Central Ltd.
Year: 2006
OAI identifier: oai:eprints.whiterose.ac.uk:2602

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