title: Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX.
abstract: Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hallmark traits of cancer, resistance to HSP90 inhibitors is possible and their ability to induce apoptosis is less than might be expected. Using an isogenic model for BAX knockout in HCT116 human colon carcinoma cells, we demonstrate the induction of BAX-dependent apoptosis at pharmacologically relevant concentrations of the HSP90 inhibitor 17-AAG both in vitro and in tumor xenografts in vivo. Removal of BAX expression by homologous recombination reduces apoptosis in vitro and in vivo but allows a lower level of cell death via a predominantly necrotic mechanism. Despite reducing apoptosis, the loss of BAX does not alter the overall sensitivity to 17-AAG in vitro or in vivo. The results indicate that 17-AAG acts predominantly to cause a cytostatic antiproliferative effect rather than cell death and further suggest that BAX status may not alter the overall clinical response to HSP90 inhibitors. Other agents may be required in combination to enhance tumor-selective killing by these promising drugs. In addition, there are implications for the use of apoptotic endpoints in the assessment of the activity of molecularly targeted agents.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
authors.forename: Marissa V
authors.initials: MV
authors.lastname: Powers
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Susana
authors.initials: S
authors.lastname: Miranda
authors.forename: Alison
authors.initials: A
authors.lastname: Maloney
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494826:BAX protein, human; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051028:bcl-2-Associated X Protein; C112765:tanespimycin