Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression
Dachs, Gabi U., Steele, Andrew J., Coralli, Claudia, Kanthou, Chryso, Brooks, Andrew C., Gunningham, Sarah P., Currie, Margaret J., Watson, Ally I., Robinson, Bridget A. and Tozer, Gillian M. (2006) Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression. BMC cancer, 6, 280. (doi:10.1186/1471-2407-6-280) (PMID:9845117)
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Description/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 |
|---|---|
| ISSN: | 1471-2407 (electronic) |
| Subjects: | R Medicine > RB Pathology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Cancer Sciences |
| ePrint ID: | 178125 |
| URI: | http://eprints.soton.ac.uk/id/eprint/178125 |
| Deposited On: | 23 Mar 2011 10:07 |
| Last Modified: | 01 Jun 2011 06:39 |
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