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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

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

Leukemia volume 18, pages 1780–1788 (2004)Cite this article

Abstract

Interactions between the cyclin-dependent kinase inhibitor flavopiridol (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 (24 h) 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-induced 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.

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Acknowledgements

These studies have been supported by awards CA CA63753, CA93738, CA100866, Leukemia and Lymphoma Society of America award 6045-03 and an award from the US Department of Defense, DOD (DAMD-17-03-1-0209).

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Author notes

  1. R R Rosato and Y Dai: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA

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

  2. Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA

    S Grant

  3. Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA

    S Grant

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  1. R R Rosato
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Correspondence to S Grant.

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Rosato, R., Dai, Y., Almenara, J. et al. Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. Leukemia 18, 1780–1788 (2004). https://doi.org/10.1038/sj.leu.2403491

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