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Updated: Jul 18, 2026
Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells
Published on: June 14, 2024
Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression
Gabi U Dachs1, Andrew J Steele, Claudia Coralli
1Angiogenesis Research Group, Department of Pathology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. gabi.dachs@chmeds.ac.nz
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.
Conclusion:
Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P.
Insights
Combretastatin A-4 phosphate (CA-4-P) affects hypoxia-inducible factor 1 (HIF-1) differently in tumors. Under hypoxia, CA-4-P reduces HIF-1, but under aerobic conditions, it increases HIF-1 and vascular endothelial growth factor (VEGF-A).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Solid tumor growth and spread depend on a functional vascular network, making it a therapeutic target.
- Combretastatin A-4 phosphate (CA-4-P) is a tubulin-depolymerizing agent investigated as a vascular disrupting agent.
- Tumor microenvironments, characterized by hypoxia, significantly influence gene regulation via hypoxia-inducible factor 1 (HIF-1).
Purpose of the Study:
- To investigate the in vitro effects of CA-4-P on the signaling pathway of HIF-1.
- To understand the molecular mechanisms of CA-4-P in the context of tumor hypoxia.
Main Methods:
- In vitro investigation of CA-4-P's impact on HIF-1 upstream and downstream signaling factors.
- Differential cell treatment under hypoxic and aerobic conditions.
Main Results:
- CA-4-P treatment under hypoxia showed a concentration-dependent reduction in HIF-1 accumulation, more pronounced in endothelial cells.
- Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions.
- Aerobic CA-4-P treatment activated nuclear factor kappaB via RhoA, leading to increased vascular endothelial growth factor A (VEGF-A) expression.
Conclusions:
- Findings elucidate the complex effects of CA-4-P on HIF-1 signaling pathways.
- This research advances the understanding of signal transduction in anti-vascular agent action.
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