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The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584.
- Source :
-
Cancer research [Cancer Res] 2004 Sep 15; Vol. 64 (18), pp. 6626-34. - Publication Year :
- 2004
-
Abstract
- Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.
- Subjects :
- Angiogenesis Inhibitors administration & dosage
Animals
Cattle
Cell Division drug effects
Cell Line, Tumor
Drug Synergism
Endothelium, Vascular cytology
Endothelium, Vascular drug effects
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors pharmacology
Gene Expression Regulation drug effects
Humans
Hydroxamic Acids administration & dosage
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Mice, Nude
Neovascularization, Pathologic drug therapy
Neovascularization, Pathologic enzymology
Neovascularization, Pathologic genetics
Phthalazines administration & dosage
Pyridines administration & dosage
Transcription Factors biosynthesis
Vascular Endothelial Growth Factor A biosynthesis
Xenograft Model Antitumor Assays
Angiogenesis Inhibitors pharmacology
Antineoplastic Combined Chemotherapy Protocols pharmacology
Histone Deacetylase Inhibitors
Hydroxamic Acids pharmacology
Phthalazines pharmacology
Pyridines pharmacology
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 64
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 15374977
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-04-0540