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Molecular Pharmacology

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Research ArticleArticle

Sequence-Dependent Potentiation of Paclitaxel-Mediated Apoptosis in Human Leukemia Cells by Inhibitors of the Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase Pathway

Chunrong Yu, Shujie Wang, Paul Dent and Steven Grant
Molecular Pharmacology July 2001, 60 (1) 143-154; DOI: https://doi.org/10.1124/mol.60.1.143
Chunrong Yu
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Shujie Wang
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Paul Dent
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Steven Grant
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This article has a correction. Please see:

  • Correction to “Sequence-dependent potentiation of paclitaxel-mediated apoptosis in human leukemia cells by inhibitors of the mitogen-activated protein kinase kinase/mitogen-activated protein kinase pathway” - August 01, 2001

Abstract

Effects of inhibitors of the mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) cascade have been examined in relation to paclitaxel-induced apoptosis in human monocytic leukemia cells (U937). Cells treated with paclitaxel (250 nm; 6 h) followed by PD98059 (40 μM; 15 h) exhibited a significant increase in mitochondrial dysfunction (e.g., cytochromec release), caspase activation, poly ADP-ribose polymerase cleavage, and apoptosis, whereas pretreatment of cells with PD98059 reduced lethality. Similar results were obtained with other MEK/MAPK inhibitors (e.g., U0126 and PD184352). Subsequent exposure of paclitaxel-treated cells to PD98059 did not enhance dephosphorylation/activation of p34cdc2 but diminished expression of the antiapoptotic protein Mcl-1. The caspase inhibitor ZVAD-fmk opposed potentiation of paclitaxel-induced loss of mitochondrial membrane potential (Δψm) and apoptosis by PD98059, but not cytochrome c release. Paclitaxel treatment induced sustained phosphorylation/activation of MAPK, an effect prevented by subsequent, but not prior, exposure to PD98059. Paclitaxel treatment also induced c-Jun N-terminal kinase phosphorylation, but this effect was enhanced only slightly by subsequent PD98059 administration. Although paclitaxel alone failed to induce p38 MAPK activation, subsequent (but not prior) exposure to PD98059 induced a dramatic increase in p38 MAPK phosphorylation. Moreover, coadministration of the p38 MAPK inhibitors SB203580 and SB202190 abrogated the increase in paclitaxel-mediated apoptosis induced by PD98059. Finally, subsequent PD98059 exposure increased, whereas prior exposure decreased inhibition of clonogenicity by paclitaxel. Together, these findings suggest that subsequent exposure of paclitaxel-treated U937 cells to MEK/MAPK inhibitors induces perturbations in signaling pathways, particularly the p42/44 MAPK and p38 MAPK cascades, that lower the threshold for mitochondrial injury and induction of cell death.

  • Abbreviations

    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated kinase
    JNK
    c-Jun N-terminal kinase
    SAPK
    stress-activated protein kinase
    PKC
    protein kinase C
    MEK
    mitogen-activated protein kinase kinase
    FCS
    fetal calf serum
    DMSO
    dimethyl sulfoxide
    TNF
    tumor necrosis factor
    PBS
    phosphate-buffered saline
    7-AAD
    7-amino actinomycin D
    PBS-T
    phosphate-buffered saline-Tween 20
    NP-40
    Nonidet P-40
    • Received December 13, 2000.
    • Accepted March 21, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Sequence-Dependent Potentiation of Paclitaxel-Mediated Apoptosis in Human Leukemia Cells by Inhibitors of the Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase Pathway

    Chunrong Yu, Shujie Wang, Paul Dent and Steven Grant
    Molecular Pharmacology July 1, 2001, 60 (1) 143-154; DOI: https://doi.org/10.1124/mol.60.1.143

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    Research ArticleArticle

    Sequence-Dependent Potentiation of Paclitaxel-Mediated Apoptosis in Human Leukemia Cells by Inhibitors of the Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase Pathway

    Chunrong Yu, Shujie Wang, Paul Dent and Steven Grant
    Molecular Pharmacology July 1, 2001, 60 (1) 143-154; DOI: https://doi.org/10.1124/mol.60.1.143
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