Dachs, GU;
Steele, AJ;
Coralli, C;
Kanthou, C;
Brooks, AC;
Gunningham, SP;
Currie, MJ;
... Tozer, GM; + view all
(2006)
Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression.
BMC Cancer
, 6
, Article 280. 10.1186/1471-2407-6-280.
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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 kappa B 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.
| Type: | Article |
|---|---|
| Title: | Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/1471-2407-6-280 |
| Publisher version: | http://dx.doi.org/10.1186/1471-2407-6-280 |
| Language: | English |
| 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. |
| Keywords: | VASCULAR-TARGETING AGENT, ENDOTHELIAL-CELLS, A4 PHOSPHATE, A-4 PHOSPHATE, KAPPA-B, SIGNAL-TRANSDUCTION, ANGIOGENESIS, CANCER, TRIAL, FACTOR-1-ALPHA |
| UCL classification: | UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/151146 |
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