title: LBH-589 (panobinostat) potentiates fludarabine anti-leukemic activity through a JNK- and XIAP-dependent mechanism.
abstract: Effects of the HDAC inhibitor LBH-589 (panobinostat) on fludarabine lethality toward acute myeloid leukemia (AML) cells were examined in vitro and in vivo. LBH-589 pretreatment sensitized U937, HL-60, and primary leukemia cells to fludarabine while blocking NF-κB activation accompanied by XIAP down-regulation and JNK activation. Pharmacologic or genetic JNK inhibition significantly attenuated LBH-589/fludarabine lethality, whereas XIAP over-expression diminished JNK activation and apoptosis. Combined in vivo treatment abrogated leukemia growth in a U937 xenograft murine model and substantially increased animal survival. These studies highlight the interplay between NF-κB activation, XIAP down-regulation, and JNK activation in anti-leukemic synergism between fludarabine and LBH-589.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA 23298, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rosato
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hock
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D000077767:Panobinostat; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D006877:Hydroxamic Acids; D007211:Indoles; D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; D000077767:Panobinostat; D048670:MAP Kinase Kinase 4; D014740:Vidarabine; C024352:fludarabine
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