Restoration of TNF-alpha-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833

Tumor necrosis factor (TNF-alpha) is a cytokine with antitumor activity against several cellular models. TNF-alpha-induced apoptosis seems to be mediated by a signaling pathway termed 'sphingomyelin-ceramide' pathway, which consists of the hydrolysis of sphingomyelin and the production of...

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Bibliographic Details
Published in:The FASEB journal 1998-01, Vol.12 (1), p.101-109
Main Authors: Bezombes, C, Maestre, N, Laurent, G, Levade, T, Bettaïeb, A, Jaffrézou, J P
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors
Cell Survival - drug effects
Cyclosporins - pharmacology
Humans
Leukemia, Myeloid - enzymology
Leukemia, Myeloid - metabolism
Leukemia, Myeloid - pathology
Sphingomyelin Phosphodiesterase - metabolism
Sphingomyelins - biosynthesis
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Tumor necrosis factor (TNF-alpha) is a cytokine with antitumor activity against several cellular models. TNF-alpha-induced apoptosis seems to be mediated by a signaling pathway termed 'sphingomyelin-ceramide' pathway, which consists of the hydrolysis of sphingomyelin and the production of its breakdown product ceramide. Our study shows that KG1a cells, which are inherently resistant to TNF-alpha and do not produce ceramide upon cytokine stimulation, can be sensitized by the use of the P-glycoprotein inhibitor PSC833. Coincubation with 1 microM of this cyclosporin derivative restored the apoptotic potential of 10 ng/ml TNF-alpha. This effect was associated with the restoration of ceramide generation (315%) and activation of neutral, but not acid sphingomyelinase activity (143%). Furthermore, we demonstrate that treatment of KG1a cells with 1 microM PSC833 led to a threefold increase in inner plasma membrane sphingomyelin content and basal neutral sphingomyelinase activity. These results support the hypothesis whereby resistance to TNF-alpha-mediated apoptosis of certain leukemic cells is linked to the disposability of the sphingomyelin pool. These data also suggest a role for P-glycoprotein in sphingomyelin transverse plasma membrane asymmetry.
ISSN:0892-6638
1530-6860
DOI:10.1096/fasebj.12.1.101