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Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK

Oncogene volume 22, pages 582–589 (2003)Cite this article

Abstract

Treatment of human promyeloleukemic HL-60 cells with the experimental antileukemic drug ajoene induces the activation of the mitogen-activated protein kinases (MAPKs) c-Jun NH2-terminal kinase (JNK), p38 and extracellular signal-regulated kinases (ERK) 1/2 as well as the survival kinase Akt. JNK activation occurred in HL-60/neo, HL-60/bcl-xL, and in HL-60 cells pretreated with the pan-caspase inhibitor zVAD-fmk, indicating that JNK activation is not dependent on ajoene-induced mitochondria perturbation and subsequent caspase activation. Cells overexpressing a dominant-negative JNK showed no altered sensitivity towards ajoene suggesting that the activation of JNK is not necessary for ajoene-induced cell death. Inhibition of p38 MAPK by SB 203580 had no influence on ajoene-mediated apoptosis. In contrast, inhibition of ERK1/2 vastly enhanced ajoene-induced cell death. The survival kinase Akt, in contrast, did not participate in ajoene-induced death signaling as shown by the use of the phosphatidylinositol-3-kinase inhibitor wortmannin. Thus in contrast to the previous findings regarding stress-induced cell death, ajoene-mediated activation of JNK and p38 has no impact on ajoene-induced apoptosis in HL-60 cells. Blockade of ERK1/2 but not Akt pathways leads to sensitization of cells against ajoene-mediated apoptosis supporting the view that inhibition of ERK1/2 is a valuable strategy to increase the sensitivity of promyeloleukemic cells towards ajoene.

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Acknowledgements

We thank S Eichhorst (Department of Medicine II, Klinikum Grosshadern, University of Munich) for critically reading the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 369).

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Authors and Affiliations

  1. Department of Pharmacy, Center of Drug Research, University of Munich, Munich, D-81377, Germany

    Dorothee S M Antlsperger, Verena M Dirsch, Dulce Ferreira & Angelika M Vollmar

  2. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Jen-Liang Su & Ming-Liang Kuo

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  1. Dorothee S M Antlsperger
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Correspondence to Verena M Dirsch.

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Antlsperger, D., Dirsch, V., Ferreira, D. et al. Ajoene-induced cell death in human promyeloleukemic cells does not require JNK but is amplified by the inhibition of ERK. Oncogene 22, 582–589 (2003). https://doi.org/10.1038/sj.onc.1206161

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