Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1alpha and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.

Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) are single-gene products that exist in separate but interconvertible forms. XOD utilizes hypoxanthine or xanthine as a substrate and O2 as a cofactor to produce superoxide (·O2 (-)) and uric acid. XDH acts on these same substrates but utilizes NAD as a cofactor to produce NADH instead of ·O2 (-) and uric acid. XOD has been proposed as a source of oxygen radicals in polymorphonuclear, endothelial, epithelial, and connective tissue cells. However, several questions remain about the physiological significance and functions of XOD on aging and oxidative stress. XOD is reported to play an important role in cellular oxidative status, detoxification of aldehydes, oxidative injury in ischemia-reperfusion, and neutrophil mediation. For example, XOD may serve as a messenger or mediator in the activation of neutrophil, T cell, cytokines, or transcription in defense mechanisms rather than as a free radical generator of tissue damage. Emerging evidence on the synergistic interactions of ·O2 (-), a toxic product of XOD and nitric oxide, may be another illustration of XOD involvement in tissue injury and cytotoxicity in an emergent condition such as ischemia or inflammation.

FK228 (formerly FR901228) was recently isolated fromChromobacterium violaceum as a potent antitumor agent and its biologic target protein was identified as histone deacetylase (HDAC). Because of its unique chemical structure (i.e., bicyclic depsipeptide) and activity profile in the National Cancer Institute's developmental therapeutics program, FK228 is currently in a phase I clinical trial for cancer therapy. In the present study, we investigated the antiangiogenic activity of FK228 in vivo and in vitro. FK228 potently blocked the hypoxia-stimulated proliferation, invasion, migration, adhesion and tube formation of bovine aortic endothelial cells at the same concentration at which the agent inhibited the HDAC activity of cells. In addition, FK228 inhibited the neovascularization of chick embryo and that of adult mice in the Matrigel plug assay. Interestingly, the expression of angiogenic-stimulating factors such as vascular endothelial growth factor or kinase insert domain receptor were suppressed by FK228, whereas that of angiogenic-inhibiting factors such as von Hippel Lindau and neurofibromin2 were induced, suggesting that a gene-transcription effect was involved in the inhibition of angiogenesis by FK228. These results indicate that FK228 is a novel antiangiogenic agent and may suppress tumor expansion, at least in part, by the inhibition of neovascularization. © 2002 Wiley-Liss, Inc. Key words: FK228; angiogenesis; histone deacetylases; antitumor agentAngiogenesis is the multistep process of new blood vessel formation by endothelial cells. The process is controlled by oppositely regulating factors that induce or suppress endothelial cell growth. The corruption of this balance is directly related with pathologic diseases such as outgrowth and spreading of cancer cells, diabetic retinopathy, rheumatoid and ischemia. 1 Extensive studies have been conducted to elucidate the mechanism and to develop therapeutic methods. Antiangiogenic agents have gathered special attention because they could be new anticancer therapeutic agents with different mode of actions from the anticancer drugs used currently. To date, several agents have been developed for this purpose. These include angiostatin, 2 endostatin 3 and canstatin 4 as endogenous peptide inhibitors and TNP-470, 5 eponemycin, 6 radicicol 7 and depudecin 8 as low molecular weight compounds from microbial metabolites and thalidomide, 9 marimastat 10 and SU6668 11 as synthetic inhibitors. Most of these agents inhibit the activity of metalloproteinases or the kinase activity of the vascular endothelial growth factor (VEGF) receptor, Flk/KDR, which are thought to be crucial and specific for the angiogenesis.Meanwhile, hypoxia is considered to be one of the key factors to trigger angiogenesis by the induction of angiogenic factors such as VEGF and hypoxia-inducible factor-1␣ (HIF-1␣). 12,13 Adaptation to hypoxia involves appropriate alterations in the expression of a number of angiogenesis-responsive genes. 14 The covalent acetylation of histones is known to play sig...

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