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

JT Nguyen, JA Wells - … of the National Academy of Sciences, 2003 - National Acad Sciences
JT Nguyen, JA Wells
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
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 …
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.
National Acad Sciences