title: Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia.
abstract: Most patients with acute myelogenous leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSC). Thus, it is imperative to identify novel therapies that can ablate LSCs. Using an in silico gene expression-based screen for compounds evoking transcriptional effects similar to the previously described anti-LSC agent parthenolide, we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor that is structurally similar to phenylbutyrate, but with improved activity at submicromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of Hsp90 to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike parthenolide, the caspase-dependent apoptosis caused by AR-42 occurs without activation of Nrf-2-driven cytoprotective pathways. As AR-42 is already being tested in early clinical trials, we expect that our results can be extended to the clinic.
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine and mlg2007@med.cornell.edu dhassane@med.cornell.edu.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine and.
authors.forename: Neng
authors.initials: N
authors.lastname: Yang
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine and.
authors.forename: Krishan K
authors.initials: KK
authors.lastname: Sharma
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester;
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Corbett
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Division of Hematology, The Comprehensive Cancer Center, College of Pharmacy, Ohio State University, Columbus, Ohio.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine and.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: Institute of Computational Biomedicine, Weill Medical College of Cornell University, New York; mlg2007@med.cornell.edu dhassane@med.cornell.edu.
authors.forename: Duane C
authors.initials: DC
authors.lastname: Hassane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007928:Lethal Dose 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D010654:Phenylbutyrates / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D012717:Sesquiterpenes; C002669:parthenolide; D020169:Caspases