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

Gabi U Dachs,Chryso Kanthou,Gillian M Tozer,Andrew J Steele,Ally I Watson,Bridget A Robinson,Andrew C Brooks,Claudia Coralli,Margaret J Currie,Sarah P Gunningham

doi:10.1186/1471-2407-6-280

Gabi U Dachs, Chryso Kanthou + Show 8 more

Open Access

https://doi.org/10.1186/1471-2407-6-280

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Abstract

BackgroundA 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.MethodsWe investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.ResultsCA-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.ConclusionOur findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.

Highlights

A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies
hypoxia inducible factor 1 (HIF-1) accumulation following hypoxic Combretastatin A-4 phosphate (CA-4-P) treatment Using Western blot analysis, we confirmed that the HIF1α subunit accumulated in T24 cells subjected to hypoxia or CoCl2 within 30 min and increased further up to a maximum at 4 h, and degraded rapidly, within 15 min, following re-oxygenation (Figure 2A)
Western blot analysis of treated cell extracts indicated a trend towards a CA-4-P concentration- dependent reduction in HIF-1 accumulation under hypoxia

Summary

Introduction

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. All solid tumours depend on a functional vascular supply for their growth, survival and metastatic spread [1]. BMC Cancer 2006, 6:280 http://www.biomedcentral.com/1471-2407/6/280 and anti-vascular agents, which target the existing tumour blood vessels (for a recent review see [2]). Combretastatin A-4 phosphate (CA-4-P), a tubulin-depolymerising agent structurally related to colchicines, is in clinical trials as a vascular disrupting agent. More rapid effects include activation of the small GTPase Rho A and subsequent reorganization of the actin cytoskeleton, leading to an increase in endothelial monolayer permeability to macromolecules [9]. Rho A has been linked to the activation of transcription factors, including NF-κB [10]

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