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

Zheng (David) Qian, Xiaofei Wang, Sushant K. Kachhap, Yukihiko Kato, Yongfeng Wei, Lu Zhang, Peter Atadja, Roberto Pili

Research output: Contribution to journalArticle

190 Citations (Scopus)

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-a 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.

Original languageEnglish (US)
Pages (from-to)6626-6634
Number of pages9
JournalCancer Research
Volume64
Issue number18
DOIs
StatePublished - Sep 15 2004
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor
Histone Deacetylase Inhibitors
Protein-Tyrosine Kinases
Neoplasms
Vascular Endothelial Growth Factor A
Endothelial Cells
Growth
Angiopoietin-2
Hypoxia-Inducible Factor 1
Chromatin Assembly and Disassembly
vatalanib
LAQ824
Acetylation
Histones
Prostate
Up-Regulation
Cell Proliferation
Breast Neoplasms
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Qian, Zheng (David); Wang, Xiaofei; Kachhap, Sushant K.; Kato, Yukihiko; Wei, Yongfeng; Zhang, Lu; Atadja, Peter; Pili, Roberto.

In: Cancer Research, Vol. 64, No. 18, 15.09.2004, p. 6626-6634.

Research output: Contribution to journalArticle

Qian, Zheng (David) ; Wang, Xiaofei ; Kachhap, Sushant K. ; Kato, Yukihiko ; Wei, Yongfeng ; Zhang, Lu ; Atadja, Peter ; Pili, Roberto. / 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. In: Cancer Research. 2004 ; Vol. 64, No. 18. pp. 6626-6634.
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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-a 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.",
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AU - Kachhap, Sushant K.

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AU - Atadja, Peter

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