title: Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: roles of XIAP and cIAPs.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it shows apoptosis-inducing activity in transformed, but not in normal, cells. As with most anticancer agents, however, its clinical use is restricted by either inherent or acquired resistance by cancer cells. We demonstrate here that small-molecule SMAC mimetics that antagonize the inhibitor of apoptosis proteins (IAP) potently sensitize previously resistant human cancer cell lines, but not normal cells, to TRAIL-induced apoptosis, and that they do so in a caspase-8-dependent manner. We further show that the compounds have no cytotoxicity as single agents. Also, we demonstrate that several IAP family members likely participate in the modulation of cellular sensitivity to TRAIL. Finally, we note that the compounds that sensitize cancer cells to TRAIL are the most efficacious in binding to X-linked IAP, and in inducing cellular-IAP (cIAP)-1 and cIAP-2 degradation. Our studies thus describe valuable compounds that allow elucidation of the signaling events occurring in TRAIL resistance, and demonstrate that these agents act as potent TRAIL-sensitizing agents in a variety of cancer cell lines.
authors.affiliation: Corresponding Author: Kristiina Vuori, Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. kvuori@sanfordburnham.org.
authors.forename: Darren
authors.initials: D
authors.lastname: Finlay
authors.forename: Mitchell
authors.initials: M
authors.lastname: Vamos
authors.forename: Marcos
authors.initials: M
authors.lastname: González-López
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Santhi Reddy
authors.initials: SR
authors.lastname: Ganji
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Trina R
authors.initials: TR
authors.lastname: Cooley
authors.forename: Curt T
authors.initials: CT
authors.lastname: Hauser
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Kristiina
authors.initials: K
authors.lastname: Vuori
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D054852:Small Molecule Libraries; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8