Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1α 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 historic 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. (C) 2002 Elsevier Science (USA). All rights reserved.