Modulation of angiogenesis-related protein synthesis by valproic acid.
Recent studies have attested to the antiangiogenic effects of HDAC inhibitors on solid human tumors. The HDAC inhibitor butyrate has been reported to impair tumor-cell-induced angiogenesis. However, due to its poor bioavailability in vivo, the therapeutic use of butyrate is limited. On the other hand, valproic acid has inhibitory effects on carcinoma cells, is known to be well tolerated, and has an excellent bioavailability. We therefore set out to investigate whether the HDAC inhibitor valproic acid also impairs angiogenesis. Our findings indicate that valproic acid represses the relevant angiogenic factors VEGF and FGF in Caco-2 cells. Both, protein expression as well as mRNA levels of VEGF, were reduced to a similar degree. Suppression of ubiquitin-proteasome activity could be a possible reason for valproic acid effects on regulatory angiogenesis proteins. These results suggest that the HDAC inhibitor valproic acid could become a valuable new addition in the attempt to develop alternative therapeutic approaches in the treatment of colon carcinomas.
Zgouras
Dimitrios
D
Second Department of Medicine, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
Becker
Ute
U
Loitsch
Stefan
S
Stein
Jürgen
J
D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; D014635:Valproic Acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex