Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells

It has been proposed that ceramide mediates anthracyclin-induced apoptosis and that drug resistance may arise due to upregulated removal of this activ e lipid through glucosylation. We report that HepG2 hepatoma cells displaye d only a modest apoptotic response to doxorubicin treatment, accompanied by a substantial elevation of ceramide levels only at toxic drug concentratio ns. 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), use d at concentrations causing a 90% inhibition of ceramide glucosylation, enh anced doxorubicin-elicited ceramide elevation, but only PDMP potentiated ap optosis. Exogenously administered ceramide had only a marginal apoptotic ef fect 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 w as still outstanding at lower concentrations, at which P-gp inhibition was no longer observed. These results demonstrate that the chemosensitizing eff ect of PDMP is, at least partly, independent from its activity as a glucosy lceramide synthase inhibitor. Moreover, P-glycoprotein inhibition is not ce ntral to the phenomenon. (C) 2001 Academic Press.