Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.

摘要: Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to lysine deacetylase or simply inhibitors, have since been recognized exert multiple cytotoxic actions in cancer cells, often acetylation of non-histone proteins. Some well-recognized mechanisms HDACI lethality include, addition relaxation DNA and de-repression gene transcription, interference with chaperone protein function, free radical generation, induction damage, up-regulation endogenous inhibitors cell cycle progression, e.g., p21, promotion apoptosis. Intriguingly, this class agents is relatively selective for transformed at least pre-clinical studies. In recent years, additional action these uncovered. For example, HDACIs interfere repair processes, well disrupt checkpoints, critical the maintenance genomic integrity face diverse genotoxic insults. Despite their potential, clinical use remains restricted certain subsets T-cell lymphoma. Currently, it appears likely that ultimate role will lie rational combinations, only a few which pursued clinic date. This review focuses on recently identified particular emphasis those relate damage response (DDR), discusses synergistic strategies combining several novel targeted DDR antagonize anti-apoptotic proteins could implications future patients cancer.