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 journalArticle

12 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 languageEnglish (US)
Pages (from-to)491-498
Number of pages8
JournalLeukemia Research
Volume36
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • AML
  • Fludarabine
  • Histone deacetylase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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