Antiangiogenic effects of the chemopreventive agent tributyrin, a butyric acid prodrug, during the promotion phase of hepatocarcinogenesis

Carcinogenesis. 2019 Aug 22;40(8):979-988. doi: 10.1093/carcin/bgy190.


Agents that inhibit angiogenic factors may prevent the development of hepatocellular carcinoma (HCC). Thus, the objective of this study was to kinetically evaluate the antiangiogenic activity of tributyrin (TB), a butyric acid prodrug, in the promotion stage of hepatocarcinogenesis. For this purpose, the resistant hepatocyte (RH) model was used for induction of preneoplastic lesions in Wistar rats. During the promotion phase, the animals received TB or maltodextrin (MD) as control daily. The rats were killed at three time-points (P1, P2 and P3). Increased expression of Vegfa and Vegfr2 was observed during promotion phase of hepatocarcinogenesis, which was not reversed by TB treatment. However, TB treatment reduced the expression of cluster of differentiation (CD) 34-positive vessels at P3 and α-smooth muscle actin (α-SMA)-positive vessels at P2 compared with MD. Enhanced levels of hypoxia inducible factor-1α (HIF-1α) and phosphorylated extracellular signal-regulated kinases (pERK) were detected at P3 when compared with P1 and P2 in the MD treatment. TB treatment reduced the levels of HIF-1α and pERK at P3 relative to the MD control. Experiments with human umbilical vein endothelial cells (HUVEC) showed that sodium butyrate (NaBu) inhibited cell migration and tube formation, confirming the antiangiogenic activity of its prodrug TB. In conclusion, antiangiogenic activity of TB is an early event that already occurs in preneoplastic livers, reinforcing its potential chemopreventive effects against HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Butyric Acid / pharmacology
  • Carcinogenesis / drug effects*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Cell Movement / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hepatocytes / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
  • Liver / drug effects
  • Liver / pathology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / pathology
  • Polysaccharides / pharmacology
  • Prodrugs / pharmacology
  • Rats
  • Triglycerides / pharmacology*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / genetics


  • Actins
  • Angiogenesis Inhibitors
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Polysaccharides
  • Prodrugs
  • Triglycerides
  • Vascular Endothelial Growth Factor A
  • smooth muscle actin, rat
  • vascular endothelial growth factor A, rat
  • Butyric Acid
  • maltodextrin
  • Kdr protein, rat
  • Vascular Endothelial Growth Factor Receptor-2
  • tributyrin