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

Dachs, G.U., Steele, A.J., Coralli, C., Kanthou, C., Brooks, A.C., Gunningham, S.P., Currie, M.J., Watson, A.I., Robinson, B.A. and Tozer, G.M. (2006) Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression. BMC Cancer, 6 (Art. N). ISSN 1471-2407

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Abstract

Background

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.

Methods

We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.

Results

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.

Conclusion

Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.

Item Type:	Article
Copyright, Publisher and Additional Information:	© 2006 Dachs et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology (Sheffield)
Depositing User:	Repository Officer
Date Deposited:	07 Aug 2007 14:31
Last Modified:	08 Feb 2013 16:54
Published Version:	http://dx.doi.org/10.1186/1471-2407-6-280
Status:	Published
Publisher:	BioMed Central Ltd.
Refereed:	Yes
Identification Number:	10.1186/1471-2407-6-280
URI:	http://eprints.whiterose.ac.uk/id/eprint/2602

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