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

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• 作者：Roberto Rosato^a ; Stefanie Hock^a ; Paul Dent^b ; ^c ; Yun Dai^a ; Steven Grant^a ; ^b ; ^c ; ^d ; ^{stgrant@vcu.edu}
• 关键词：AML ; acute myelogenous leukemia ; CLL ; chronic lymphocytic leukemia ; CTCL ; cutaneous T-cell lymphoma ; LBH-589 ; panobinostat ; FdA ; fludarabine ; HDACI ; histone deacetylase inhibitor ; XIAP ; X chromosome-linked inhibitor of apoptosis ; JNK ; c-Jun N-terminal kin
• 刊名：Leukemia Research
• 出版年：2012
• 期刊代码：186_01452126
• 类别：med
• 出版时间：April, 2012
• 卷：36
• 期：4
• 页码：491-498
• 文件大小：1279 K

摘要

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-魏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-魏B activation, XIAP down-regulation, and JNK activation in anti-leukemic synergism between fludarabine and LBH-589.