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(The FASEB Journal. 1998;12:101-109.)
© 1998 FASEB

RESEARCH COMMUNICATION

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

Christine Bezombesa, Nicolas Maestrea, Guy Laurenta,b, Thierry Levadec, Ali Bettaïeba, and Jean-Pierre Jaffrézoua,1

a CJF INSERM 9503, Centre Claudius Régaud, Toulouse Cédex 31052, France
b Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Toulouse 31059, France
c Laboratoire de Biochimie Médicale, INSERM 466, Centre Hospitalier Universitaire Rangueil, Toulouse 31403, France

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 µM 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 µM 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.— Bezombes, C., Maestre, N., Laurent, G., Levade, T., Bettaïeb, A., Jaffrézou, J.-P. Restoration of TNF-{alpha}-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833. FASEB J. 12, 101–109 (1998)


Key Words: TNF-{alpha} • sphingomyelin asymmetry • sphingomyelinase • ceramide




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