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

Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression
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 ?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.
1471-2407
280
Dachs, Gabi U.
6b227831-3df0-48cd-904c-0898d4b758dd
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Coralli, Claudia
4af7cd80-b7ee-4847-a8d3-982087c5c96b
Kanthou, Chryso
bdac8aa7-e27d-464d-9255-4513f2f7f623
Brooks, Andrew C.
3ba60f75-f1f4-4361-84fa-470be4b3ec29
Gunningham, Sarah P.
2e6d7858-3ecb-4236-a394-a60dad9afe88
Currie, Margaret J.
ce37908d-b423-45e0-ad35-dcacdcf22436
Watson, Ally I.
f3714adb-b5d6-45ff-86dc-77e6bb5a155e
Robinson, Bridget A.
e2c035bd-84f3-42e6-a41e-ec370b2bda00
Tozer, Gillian M.
c963e0e4-c1d0-43c8-a7a5-dc0a8dbe2557
Dachs, Gabi U.
6b227831-3df0-48cd-904c-0898d4b758dd
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Coralli, Claudia
4af7cd80-b7ee-4847-a8d3-982087c5c96b
Kanthou, Chryso
bdac8aa7-e27d-464d-9255-4513f2f7f623
Brooks, Andrew C.
3ba60f75-f1f4-4361-84fa-470be4b3ec29
Gunningham, Sarah P.
2e6d7858-3ecb-4236-a394-a60dad9afe88
Currie, Margaret J.
ce37908d-b423-45e0-ad35-dcacdcf22436
Watson, Ally I.
f3714adb-b5d6-45ff-86dc-77e6bb5a155e
Robinson, Bridget A.
e2c035bd-84f3-42e6-a41e-ec370b2bda00
Tozer, Gillian M.
c963e0e4-c1d0-43c8-a7a5-dc0a8dbe2557

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)

Record type: Article

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 ?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.

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Published date: 7 December 2006

Identifiers

Local EPrints ID: 178125
URI: https://eprints.soton.ac.uk/id/eprint/178125
ISSN: 1471-2407
PURE UUID: a7fd3b53-9829-474e-83f0-958a5dbb9b05
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 23 Mar 2011 10:07
Last modified: 06 Jun 2018 12:31

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Contributors

Author: Gabi U. Dachs
Author: Claudia Coralli
Author: Chryso Kanthou
Author: Andrew C. Brooks
Author: Sarah P. Gunningham
Author: Margaret J. Currie
Author: Ally I. Watson
Author: Bridget A. Robinson
Author: Gillian M. Tozer

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