Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity.
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.
Mie Lee
You
Y
Angiogenesis Research Laboratory, Research Institute of Phamaceutical Sciences and College of Pharmacy, Seoul National University, South Korea.
Kim
Se-Hee
SH
Kim
Hae-Sun
HS
Jin Son
Myung
M
Nakajima
Hidenori
H
Jeong Kwon
Ho
H
Kim
Kyu-Won
KW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D047630:Depsipeptides; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010456:Peptides, Cyclic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C087123:romidepsin