title: Direct activation of the apoptosis machinery as a mechanism to target cancer cells.
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.
authors.affiliation: Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Nguyen
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002474:Cell-Free System; D002850:Chromatography, Gel; D003574:Cytochrome c Group / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D034741:RNA, Small Interfering; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases