Novel Histone Deacetylase Inhibitors

摘要

HDAC (histone deacetylase) is a novel target for anti-cancer drug discovery. A database of guinoline compounds was characterized for the ability to inhibit HDAC, promote differentiation and cell death in tissue culture lines of human breast cancer. Antimalarials, chloroquine and quinidine promote breast tumor cell differentiation and cell death. A novel mechanism, regulation of HDAC1 by stimulating ubiguitination and proteasomal degradation of HDAC1 is proposed to explain the actions of antimalarials in breast cancer. NSC 3852 and NSC 10010 are novel breast tumor differentiation agents. NSC 3852 inhibits HDAC enzyme activity in vitro. NSC 10010 causes differentiation by a unique mechanism, and does not inhibit HDAC activity or stimulate HDAC1 ubiquitination. We conclude that these novel compounds hold promise for breast cancer treatment and because of their independent mechanisms of action, may be even more active in combination than when used as single agents.