Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity

Biochem Biophys Res Commun. 2003 Jan 3;300(1):241-6. doi: 10.1016/s0006-291x(02)02787-0.

Abstract

Hypoxia is generally detected in central regions of solid tumors and regulates a variety of transcription factors including hypoxia-inducible factor-1 (HIF-1). HIF-1 plays a pivotal role in cellular response to low oxygen concentration, such as angiogenesis in tumor. Here, we found that a histone deacetylase (HDAC) inhibitor, FK228, inhibits the induction and activity of HIF-1 in response to hypoxia. Moreover, FK228 significantly suppressed the induction of vascular endothelial growth factor (VEGF) under hypoxia, suggesting that FK228 contributes to the inhibition of tumor angiogenesis. In Lewis lung carcinoma model, FK228 also blocked angiogenesis induced by hypoxia. These results suggest that FK228 can downregulate hypoxia-responsive angiogenesis through suppression of HIF-1alpha activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Depsipeptides*
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Histone Deacetylase Inhibitors*
  • Hypoxia / complications*
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / pathology
  • Lymphokines / genetics
  • Lymphokines / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Peptides, Cyclic*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Anti-Bacterial Agents
  • Depsipeptides
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Peptides, Cyclic
  • RNA, Messenger
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • romidepsin