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Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7533-8. Epub 2003 Jun 13.

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

Author information

1
Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Abstract

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.

PMID:
12808146
PMCID:
PMC164621
DOI:
10.1073/pnas.1031631100
[Indexed for MEDLINE]
Free PMC Article

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