Evaluation of the eventual involvement of apoptosis and H2AX histone phosphorylation on chemopreventive activity of tributyrin during different phases of rat hepatocarcinogenesis

• Grant number: 12/04760-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2012
• End date: December 31, 2012
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Fernando Salvador Moreno
• Grantee: Laura Helena Gasparini Fernandes
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hepatocellular carcinoma is responsible for millions of deaths annually and chemoprevention has been considered an important and essential approach for the control of this disease. Therefore chemoprevention can be defined as the administration of one or more compounds during the initial phases of carcinogenesis. Tributyrin (TB), a butyric acid (BA) prodrug, present in fat milk and honey, when administered to Wistar rats continuously during the initiation and promotion phases or only during the promotion phase acted as a promising chemopreventive agent of hepatocarcinogenesis. In both experiments, it was noted that the administration of TB resulted in liver histone H3K9 hyperacetylation specifically in preneoplastic lesions (PNL), as well as, increased p21 expression, which can be associated with its inhibitory effects of histone deacetylases (HDACs). Moreover, in both experiments TB induced apoptosis specifically in PNL. Histone deacetylase inhibitors (HDACi) have been studied as potential anti-neoplastic agents. These compounds are capable of modulating epigenetic mechanisms, such as histone acetylation and methylation, which may contribute to the control of gene expression in carcinogenesis. Recently, it was found that HDACi can also act to maintain the phosphorylation of H2AX, an epigenetic modification that may be associated with apoptosis induction. Thus, the goal of the present study is to assess if TB chemopreventive activity is related to apoptosis induction, and caspase-3 activation and if the epigenetic mechanism of H2AX phosphorylation could be related to this event. (AU)