Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer.

This issue of Molecular Medicine contains 14 original research reports and state-of-the-art reviews on histone deacetylase inhibitors (HDACi's), which are being studied in models of a broad range of diseases not related to the proapoptotic properties used to treat cancer. The spectrum of these diseases responsive to HDACi's is for the most part due to several antiinflammatory properties, often observed in vitro but importantly also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine postreceptor signaling. Distinct from their use in cancer, the reduction in inflammation by HDACi's is consistently observed at low concentrations compared with the higher concentrations required for killing tumor cells. This characteristic makes HDACi's attractive candidates for treating chronic diseases, since low doses are well tolerated. For example, low oral doses of the HDACi givinostat have been used in children to reduce arthritis and are well tolerated. In addition to the antiinflammatory properties, HDACi's have shown promise in models of neurodegenerative disorders, and HDACi's also hold promise to drive HIV-1 out of latently infected cells. No one molecular mechanism accounts for the non-cancer-related properties of HDACi's, since there are 18 genes coding for histone deacetylases. Rather, there are mechanisms unique for the pathological process of specific cell types. In this overview, we summarize the preclinical data on HDACi's for therapy in a wide spectrum of diseases unrelated to the treatment of cancer. The data suggest the use of HDACi's in treating autoimmune as well as chronic inflammatory diseases.