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Molecular Targets for Therapy

Caspase-dependent and -independent cell death of Jurkat human leukemia cells induced by novel synthetic ceramide analogs

Leukemia volume 20, pages 392–399 (2006)Cite this article

Abstract

Ceramide metabolism has emerged as a potential target for anticancer therapy. Here, the potential usefulness of two novel synthetic ceramide analogs as anti-leukemic drugs was investigated. Compounds AD2646 and AD2687 were able to dose-and time-dependently decrease the viability of Jurkat leukemic cells. This was accompanied by an accumulation of endogenous ceramide owing to perturbed ceramide metabolism. Cytotoxicity involved caspase activation but also necrotic-like features, as evidenced by phosphatidylserine externalization, membrane permeability, hypodiploidy, caspase processing and only partial protection from cell death by a pan-caspase inhibitor. Ceramide analogs also induced cell death in Jurkat mutants that are deficient in cell death signaling proteins, including FADD, caspase-8 and 10, and RIP. While overexpression of Bcl-xL did not suppress ceramide accumulation, it conferred robust protection from caspase activation and cell death. Altogether, these novel ceramide analogs are able to kill leukemic cells through distinct pathways implicating caspase activation and mitochondrial events, and represent a new group of bioactive molecules with potential applications in anticancer therapy.

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Abbreviations

DEVD-AMC:

Ac-Asp-Glu-Val-Asp-aminomethylcoumarin

FCS:

fetal calf serum

GlcCer:

glucosylceramide

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

SM:

sphingomyelin

TLC:

thin layer chromatography

z-VAD-fmk:

benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

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Acknowledgements

We thank Dr O Cuvillier (INSERM U.466, Toulouse) for providing Jurkat/neo and Jurkat/Bcl-xL clones. The technical assistance of N Therville is acknowledged. This study was supported by grant 607/02 from the Israel Science Foundation (to AD and SG), INSERM (to DM, SC, BS and TL) and ARC 3417 (to BS).

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Author notes

  1. T Granot, D Milhas, S Gatt and T Levade: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel

    T Granot, A Dagan & S Gatt

  2. INSERM, U466, and Laboratoire de Biochimie, CHU Rangueil, Toulouse, France

    D Milhas, S Carpentier, B Ségui & T Levade

Authors
  1. T Granot
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  2. D Milhas
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  4. A Dagan
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Correspondence to T Levade.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

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Granot, T., Milhas, D., Carpentier, S. et al. Caspase-dependent and -independent cell death of Jurkat human leukemia cells induced by novel synthetic ceramide analogs. Leukemia 20, 392–399 (2006). https://doi.org/10.1038/sj.leu.2404084

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