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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 type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2012
Effective date (End): December 31, 2012
Field of knowledge:Health Sciences - Nutrition - Nutrition Biochemistry
Principal Investigator:Fernando Salvador Moreno
Grantee:Laura Helena Gasparini Fernandes
Home 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 have been considered an important and essential approach for the control of this disease. Therefore the 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 on liver histone H3K9 hyperacetylation specifically in preneoplastic lesions (PNL), as well as, increased on 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 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, caspase-3 activation and if the epigenetic mechanism of H2AX phosphorylation could be related to this event.