title: Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia.
abstract: Treatment options for chronic lymphocytic leukaemia (CLL) are limited and eventually fail because of the development of toxicities or drug resistance. Thus, identification of new therapeutic strategies and targets is a high priority. The semisynthetic geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90 (Hsp90) binding to client proteins, thereby leading to their degradation. We demonstrate that at biologically active and clinically attainable levels (1 mumol/l), 17-AAG treatment of CLL B cells in vitro causes modest apoptosis as well as decreased AKT protein levels. Given the potential activation of AKT following antibody therapy in CLL, we evaluated the combination of 17-AAG and rituximab. These agents produced synergistic cytotoxicity of CLL cells in vitro. However, rituximab-mediated antibody-dependent cellular cytotoxicity was modestly reduced with 17-AAG, and complement-dependent cytotoxicity was not altered. We conclude that the combination of Hsp90 inhibitors with therapeutic antibodies, such as rituximab may represent a novel strategy to enhance therapeutic response in CLL. Furthermore, our data indicates that AKT and Hsp70 protein levels are relevant pharmacodynamic endpoints to monitor the in vivo effect of 17-AAG therapy.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA. amy.johnson@osumc.edu
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Cheney
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Sara K
authors.initials: SK
authors.lastname: Guster
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069283:Rituximab; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D000069283:Rituximab; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt