Modulation of angiogenesis-related protein synthesis by valproic acid

Recent studies have attested to the antiangiogenic effects of HDAC inhibitors oil solid human tumors. The HDAC inhibitor butyrate has been reported to impair tumor-cell-induced angiogenesis. However, due to its poor bioavailibility 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 bioavailibility. 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 ubiquitill-proteasome activity could be a possible reason for valproic acid effects oil 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. (C) 2004 Elsevier Inc. All rights reserved.