Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression
Dachs, Gabi U.
Steele, Andrew J.
Brooks, Andrew C.
Gunningham, Sarah P.
Currie, Margaret J.
Watson, Ally I.
Robinson, Bridget A.
Tozer, Gillian M.
- Publisher: BIOMED CENTRAL LTD
(issn: 1471-2407, eissn: 1471-2407)
Genetics | Research Article | RC254-282 | VASCULAR-TARGETING AGENT, ENDOTHELIAL-CELLS, A4 PHOSPHATE, A-4 PHOSPHATE, KAPPA-B, SIGNAL-TRANSDUCTION, ANGIOGENESIS, CANCER, TRIAL, FACTOR-1-ALPHA | Cancer Research | Oncology | Neoplasms. Tumors. Oncology. Including cancer and carcinogens
<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 <it>in vitro</it>.</p> <p>Results</p> <p>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 <it>in vitro</it>. 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.</p> <p>Conclusion</p> <p>Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.</p>