Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis.
FK228 (formerly FR901228) was recently isolated from Chromobacterium 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.
Kwon
Ho Jeong
HJ
Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, 98 Kunja-dong, Kwangjin-ku, Seoul, 143-747, Korea. kwonhj@sejong.ac.kr
Kim
Myoung Sook
MS
Kim
Min Jung
MJ
Nakajima
Hidenori
H
Kim
Kyu-Won
KW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D002986:Clinical Trials as Topic; D003094:Collagen / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D025581:Neurofibromin 2 / Q000378:metabolism; D010456:Peptides, Cyclic; D011509:Proteoglycans / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D047630:Depsipeptides; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007797:Laminin; D025581:Neurofibromin 2; D010456:Peptides, Cyclic; D011509:Proteoglycans; D025521:Tumor Suppressor Proteins; C059485:matrigel; D003094:Collagen; C087123:romidepsin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006655:Histone Deacetylases; D008025:Ligases; C497446:VHL protein, human