EVALUATION OF HDACs INHIBITORS IN CANCER CACHEXIA AND ASSOCIATED CARDIOVASCULAR COMPLICATIONS

Abstract

BACKGROUND AND OBJECTIVE: Cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass with loss of fat mass, and progressive functional impairment which cannot be fully reversed by conventional nutrition support. Cancer patients lose either half or one third or more than 5% of their original body weight which is a criteria for defining cachexia. Cachexia is an energy wasting syndrome that causes skeletal muscle wasting and skeletal muscle atrophy. Emphasis is given to the inflammatory cascade activation and their responses to the tumor growth, which seems to trigger many of the metabolic changes which are associated with muscle wasting syndrome. HDACs, as one of the epigenetic mechanisms, play a central role in the regulation of cellular properties that are related to development and progression of cancer. Several contrasting reports are available with respect to role of HDACs in skeletal muscle wasting and atrophy in disease like sarcopenia. However, there are starking difference between cachexia muscle wasting and sarcopenic skeletal muscle wasting. Limited information is available with respect to role of HDACs inhibitors in cancer cachexia which needs to be studied. Additionally, cancer cachexia induced atrophy of heart occurs by activating the signaling pathway which governs the protein synthesis and degradation. Different classes of HDAC exerts differential cardiac effects, we speculate that different classes of HDACs may have different effects in cancer cachexia and also in cardiovascular complications of cancer cachexia. Hence, we have selected entinostat (MS275) selective as class I HDACs inhibitor, MC1568 selective class II HDACs inhibitor and sodium butyrate as non-specific HDACs inhibitor to study their effects in cancer cachexia and their cardiovascular complications. The objective of the study is to evaluate the effect of different HDACs on cancer cachexia and its cardiovascular complication. To developed a therapeutic strategy for cardiovascular complications.