A CLASS OF HYBRID POLAR INDUCERS OF TRANSFORMED-CELL DIFFERENTIATION INHIBITS HISTONE DEACETYLASES

Hybrid polar compounds (HPCs) have been synthesized that induce termin al differentiation and/or apoptosis in various transformed cells. We h ave previously reported on the development of the second-generation HP Cs suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid b ishydroxamide (CBHA) that are 2,000-fold more potent inducers on a mol ar basis than the prototype HPC hexamethylene bisacetamide (HMBA). Her ein we report that CBHA and SAHA inhibit histone deacetylase 1 (HDAC1) and histone deacetylase 3 (HDAC3) activity in vitro. Treatment of cel ls in culture with SAHA results in a marked hyperacetylation of histon e H4, but culture with HMBA does not. Murine erythroleukemia cells dev eloped for resistance to SAHA are cross-resistant to trichostatin A, a known deacetylase inhibitor and differentiation inducer, but are not cross-resistant to HMBA. These studies show that the second-generation HPCs, unlike HMBA, are potent inhibitors of HDAC activity. In this se nse, HMBA and the second-generation HPCs appear to induce differentiat ion by different pathways.