Direct activation of the apoptosis machinery as a mechanism to target cancer cells

Apoptosis plays a pivotal role in the cytotoxic activity of most chemotherapeutic drugs, and defects in this pathway provide a basis for drug resistance in many cancers. Thus the ability to restore Apoptosis by using small molecules could have important therapeutic implications. Using a cell-free assay to simultaneously target multiple components of the Apoptosis pathway, we identified a class of compounds that activate caspases in a cytochrome c-dependent manner and induce Apoptosis in whole cells. By reconstituting the Apoptosis pathway with purified proteins, we determined that these compounds promote the protein-protein association of Apaf-1 into the functional apoptosome. These compounds exert cytostatic and cytotoxic effects on a variety of Cancer cell lines while having little or no activity against the normal cell lines tested. These findings suggest that direct activation of the basic Apoptosis machinery may be a viable mechanism to selectively target Cancer.