PMID: 9438415Jan 23, 1998Paper

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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
C BezombesJ P Jaffrézou

Abstract

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 mem...Continue Reading

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis