title: 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition.
abstract: The HSP90 client chaperone interaction stabilizes several important enzymes and antiapoptotic proteins, and pharmacologic inhibition of HSP90 results in rapid client protein degradation. Therefore, HSP90 inhibition is an attractive therapeutic approach when this protein is active, a phenotype commonly observed in transformed but not normal cells. However, preclinical studies with HSP90 inhibitors such as 17-AAG demonstrated depletion of only a subset of client proteins and very modest tumor cytotoxicity in chronic lymphocytic leukemia (CLL) cells. Herein, we describe another HSP90 inhibitor, 17-DMAG, which is cytotoxic to CLL but not normal lymphocytes. Treatment with 17-DMAG leads to depletion of the HSP90 client protein IKK, resulting in diminished NF-kappaB p50/p65 DNA binding, decreased NF-kappaB target gene transcription, and caspase-dependent apoptosis. Furthermore, treatment with 17-DMAG significantly decreased the white blood cell count and prolonged the survival in a TCL1-SCID transplant mouse model. The ability of 17-DMAG to function as an NF-kappaB inhibitor is of great interest clinically, as few currently available CLL drugs target this transcription factor. Therefore, the effect of 17-DMAG on NF-kappaB signaling pathways represents a novel therapy warranting further clinical pursuit in this and other B-cell lymphoproliferative disorders.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center at the Ohio State University, 410West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lin
authors.forename: Kami J
authors.initials: KJ
authors.lastname: Maddocks
authors.forename: William H
authors.initials: WH
authors.lastname: Towns
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Goettl
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Chelsey A
authors.initials: CA
authors.lastname: Raymond
authors.forename: Derek A
authors.initials: DA
authors.lastname: West
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D051550:I-kappa B Kinase; D020169:Caspases