title: Para-NO-aspirin inhibits NF-κB and induces apoptosis in B-cell progenitor acute lymphoblastic leukemia.
abstract: Although patients with acute lymphoblastic leukemia (ALL) usually achieve complete remission, disease relapse is common and difficult to treat. Para-NO-aspirin (para-NO-ASA) is a novel drug with demonstrated efficacy against a number of solid tumors and most recently chronic lymphocytic leukemia. In this study, we used ALL cell lines to assess the effects on cell viability by flow cytometry and investigated the mechanism of cell death using chemical inhibitors of key molecules and assessed the effects by flow cytometry, electrophoretic mobility shift assay, Western blotting, and quantitative reverse transcription polymerase chain reaction. Para-NO-ASA induced cell death in the pre-B ALL cell lines in association with increased reactive oxygen species, and suppression of nuclear factor-κB (NF-κB) activity. Chemical inhibitors of NF-κB similarly induced apoptosis in ALL cells, suggesting a role for suppression of NF-κB in para-NO-ASA-induced cell death. Modulation of NF-κB was not via regulation of IκB but potentially through suppression of ROCK1 and loss of reduced glutathione. Our results demonstrate that para-NO-ASA potently induces apoptosis in B-lineage ALL cells via a reactive oxygen species-dependent mechanism that is associated with suppression of NF-κB activity.
authors.affiliation: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Naveed I
authors.initials: NI
authors.lastname: Khan
authors.forename: Adam
authors.initials: A
authors.lastname: Cisterne
authors.forename: Rana
authors.initials: R
authors.lastname: Baraz
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D009363:Neoplasm Proteins; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C098312:nitroxy-butyl-acetylsalicylic acid; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D020169:Caspases; D005978:Glutathione; D001241:Aspirin