Novel Histone Deacetylase Inhibitors.

摘要

Advanced breast cancer is not curable by existing treatment regimens. The purpose of this project is to discover new drugs to treat breast cancer that act to restore the differentiated and non-growing state of breast tumor cells by inhibition of histone deacetylase. We screened a series of antitumor antimalarial drugs as well as Structural analogs of antimalarials. Our work identified 5 novel quinolines that were more potent and efficacious than the antitumor antimalarial drugs in arresting the growth of human breast tumor cells in culture. These are NSC3852,NSc69603, Nsc8637l,NscloolO, and NSC305819. Of these 5 compounds, only NSC3852 was a direct inhibitor of histone deacetylase activity, an established mechanism for induction of differentiation in breast tumor cells. Further experimentation showed a second mechanism of action of NSC3852 that contributed importantly to inhibition of tumor cell growth inhibition. NSC3852 is a redox active Compound that %enerates superoxide radicals in tumor cells and causes DNA strand breakage. The %echanism of action of the other 4 compounds involves accumulation of pRb in its hypophosphorylated state and a down-regulation of %2F1 protein levels associated with blockade-of cell growth in GI phase of the cell cycle.