Abstract
Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramide-mediated killing of different B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or gamma-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a specific, but unidentified, cellular target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors
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Antineoplastic Agents / pharmacology
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Apoptosis
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Caspase 3
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Caspases / drug effects
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Caspases / metabolism
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Cell Death / drug effects
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Ceramidases
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Enzyme Inhibitors / pharmacology
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Gamma Rays
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Leukemia, Lymphocytic, Chronic, B-Cell / radiotherapy
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Lymphocytes / drug effects*
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Lymphocytes / pathology*
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Lymphocytes / radiation effects
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Myristates / pharmacology
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Propanolamines / pharmacology
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Protein Biosynthesis
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Proteins / drug effects
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Vidarabine / analogs & derivatives
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Vidarabine / pharmacology
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bcl-2-Associated X Protein
Substances
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Antineoplastic Agents
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BAX protein, human
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Enzyme Inhibitors
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Myristates
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N-acetylsphingosine
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Propanolamines
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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2-(N-myristoylamino)-1-phenyl-1-propanol
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CASP3 protein, human
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Caspase 3
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Caspases
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Amidohydrolases
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Ceramidases
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Vidarabine
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Sphingosine
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fludarabine