Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression.
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 kappaB 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.


CONCLUSIONS
Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.
Dachs
Gabi U
GU
Angiogenesis Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. gabi.dachs@chmeds.ac.nz
Steele
Andrew J
AJ
Coralli
Claudia
C
Kanthou
Chryso
C
Brooks
Andrew C
AC
Gunningham
Sarah P
SP
Currie
Margaret J
MJ
Watson
Ally I
AI
Robinson
Bridget A
BA
Tozer
Gillian M
GM
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D051793:Hypoxia-Inducible Factor 1; D013267:Stilbenes; C058728:fosbretabulin