[Sunesis -- Novel anti-cancer concept]
>>Published online before print June 13, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.1031631100
Biochemistry
Direct activation of the apoptosis machinery as a mechanism to target cancer cells
Jack T. Nguyen and James A. Wells *
Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080
Communicated by William F. DeGrado, University of Pennsylvania School of Medicine, Philadelphia, PA, March 20, 2003 (received for review January 31, 2003)
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.<<
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