Potent antileukemia interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

R. R. Rosato, Y. Dai, J. A. Almenara, S. C. Maggio, S. T. Grant

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Interactions between the cyclin-dependent kinase inhibitor flavoiridol (FP) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-incluced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-xL, or a phosphorylation loop-deleted form of Bcl-2 (ΔBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FP-mediated XIAP downregulation.

Original languageEnglish (US)
Pages (from-to)1780-1788
Number of pages9
JournalLeukemia
Volume18
Issue number11
DOIs
StatePublished - Nov 2004

Keywords

  • Apoptosis
  • Flavopiridol
  • TRAIL
  • XIAP

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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