LBH-589 (panobinostat) potentiates fludarabine anti-leukemic activity through a JNK- and XIAP-dependent mechanism

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-kappa B 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-kappa B activation, XIAP down-regulation, and JNK activation in anti-leukemic synergism between fludarabine and LBH-589. (C) 2011 Elsevier Ltd. All rights reserved.