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

Roberto Rosato; Stefanie Hock; Paul Dent; Yun Dai; Steven Grant

doi:10.1016/j.leukres.2011.10.020

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

Roberto Rosato, Stefanie Hock, Paul Dent, Yun Dai, Steven Grant

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	491-498
Number of pages	8
Journal	Leukemia Research
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.leukres.2011.10.020
State	Published - Apr 2012

Keywords

AML
Fludarabine
Histone deacetylase inhibitor

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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10.1016/j.leukres.2011.10.020

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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.",

keywords = "AML, Fludarabine, Histone deacetylase inhibitor",

author = "Roberto Rosato and Stefanie Hock and Paul Dent and Yun Dai and Steven Grant",

note = "Funding Information: This work was supported by awards CA93738, CA100866, CA130805, and CA142509 from the National Institutes of Health and award R6181-10 from the Leukemia and Lymphoma Society of America . ",

year = "2012",

month = apr,

doi = "10.1016/j.leukres.2011.10.020",

language = "English (US)",

volume = "36",

pages = "491--498",

journal = "Leukemia Research",

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T1 - LBH-589 (panobinostat) potentiates fludarabine anti-leukemic activity through a JNK- and XIAP-dependent mechanism

AU - Rosato, Roberto

AU - Hock, Stefanie

AU - Dent, Paul

AU - Dai, Yun

AU - Grant, Steven

N1 - Funding Information: This work was supported by awards CA93738, CA100866, CA130805, and CA142509 from the National Institutes of Health and award R6181-10 from the Leukemia and Lymphoma Society of America .

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

KW - AML

KW - Fludarabine

KW - Histone deacetylase inhibitor

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U2 - 10.1016/j.leukres.2011.10.020

DO - 10.1016/j.leukres.2011.10.020

M3 - Article

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AN - SCOPUS:84857232181

VL - 36

SP - 491

EP - 498

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

IS - 4

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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