S. Di Bartolomeo et A. Spinedi, Differential chemosensitizing effect of two glucosylceramide synthase inhibitors in hepatoma cells, BIOC BIOP R, 288(1), 2001, pp. 269-274
Citations number
30
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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.