It has been proposed that ceramide mediates anthracyclin-induced apoptosis and that drug resistance may arise due to upregulated removal of this active lipid through glucosylation. We report that HepG2 hepatoma cells displayed only a modest apoptotic response to doxorubicin treatment, accompanied by a substantial elevation of ceramide levels only at toxic drug concentrations. D,L-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol (PDMP) and D,L-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), used at concentrations causing a 90% inhibition of ceramide glucosylation, enhanced doxorubicin-elicited ceramide elevation, but only PDMP potentiated apoptosis. Exogenously administered ceramide had only a marginal apoptotic effect on HepG2 cells; moreover, even in this case, apoptosis was propagated by PDMP but not by PPPP. PDMP moderately inhibited P-glycoprotein activity only at the highest concentration tested, but its chemosensitizing effect was still outstanding at lower concentrations, at which P-gp inhibition was no longer observed. These results demonstrate that the chemosensitizing effect of PDMP is, at least partly, independent from its activity as a glucosylceramide synthase inhibitor. Moreover, P-glycoprotein inhibition is not central to the phenomenon. (C) 2001 Academic Press.

Di Bartolomeo S., S.A. (2001). Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 288(1), 269-274 [10.1006/bbrc.2001.5748].

Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells

DI BARTOLOMEO, SABRINA;SPINEDI, ANGELO
2001

Abstract

It has been proposed that ceramide mediates anthracyclin-induced apoptosis and that drug resistance may arise due to upregulated removal of this active lipid through glucosylation. We report that HepG2 hepatoma cells displayed only a modest apoptotic response to doxorubicin treatment, accompanied by a substantial elevation of ceramide levels only at toxic drug concentrations. D,L-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol (PDMP) and D,L-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), used at concentrations causing a 90% inhibition of ceramide glucosylation, enhanced doxorubicin-elicited ceramide elevation, but only PDMP potentiated apoptosis. Exogenously administered ceramide had only a marginal apoptotic effect on HepG2 cells; moreover, even in this case, apoptosis was propagated by PDMP but not by PPPP. PDMP moderately inhibited P-glycoprotein activity only at the highest concentration tested, but its chemosensitizing effect was still outstanding at lower concentrations, at which P-gp inhibition was no longer observed. These results demonstrate that the chemosensitizing effect of PDMP is, at least partly, independent from its activity as a glucosylceramide synthase inhibitor. Moreover, P-glycoprotein inhibition is not central to the phenomenon. (C) 2001 Academic Press.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/09
English
Con Impact Factor ISI
Apoptosis; Ceramide; Doxorubicin; Glucosylceramide synthase; HepG2 cells; P-glycoprotein
Di Bartolomeo S., S.A. (2001). Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 288(1), 269-274 [10.1006/bbrc.2001.5748].
DI BARTOLOMEO, S; Spinedi, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/54826
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