Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Histone Deacetylases: Anti-Angiogenic Targets in Cancer Therapy

Author(s): D. Mottet, V. Castronovo.

Abstract:

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidence shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro-angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy.

Keywords: Epigenetic, histone deacetylases, tumor angiogenesis, HIF-1, histone deacetylases (HDAC), sodium butyrate, trichostatin, linker DNA, HAT (histone acetyltransferases), Phylogenetic analyses, mitochondrial, Cyclic peptides, Synthetic benzamides, cellular hypoxia, hydroxylation, pVHL, HIF-1 ubiquitination, proteosomal degradation, apoptosis, cytoskeletal reorganization, endothelial nitric oxide synthase (eNOS), migration, CXCR4, morphology, embryogenesis, PKD, Belinostat, Romidepsin, diarrhea, myelosuppression, Panobinostat, Hydroxamic Acid, myelodysplatic syndrome, hypophosphatemia, neurological toxicity, hematological disorders, Hodgkin lymphoma, peripheral T cell lymphomas, pharmacodynamic, irinotecan, methyltransferases, 5-azacitidine, pharmacokinetic profiles, phosphorylation, ARNT, EGFR, MDS, Tie2

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Article Details

VOLUME: 10
ISSUE: 8
Year: 2010
Page: [898 - 913]
Pages: 16
DOI: 10.2174/156800910793358014
Price: $58