We have previously reported that HepG2 human hepatocarcinoma cells are sensitized to doxorubicin-induced apoptosis by the glucosylceramide synthase inhibitor D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) but not by the more specific inhibitor D,L-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP). Herein we investigated whether the chemosensitizing action of PDMP impinged on any unspecific effect of this compound on doxorubicin-induced expression of p53 and/or P21(Cip1/Waf1), namely two proteins reported to modulate the apoptotic response to DNA-damaging agents, in a positive or negative fashion, respectively. We show that, in HepG2 cells, PDMP did not substantially affect doxorubicin-induced p53 upregulation, whereas drug-evoked upregulation of p21(Cip1/Waf1) was markedly attenuated. Although this outcome could be expected to account for the chemosensitizing effect of PDMP, impaired upregulation of p21(Cip1/Waf1), in the setting of unaltered p53 expression, was also observed in the case of PPPP. These results, while raising the possibility of a link between attenuation of drug-evoked p21(Cip1/Waf1) expression and redirection of (glyco)sphingolipid metabolism, show that, differently from other tumor systems, attenuation of doxorubicin-induced p21(Cip1/Waf1) expression is at least not sufficient to sensitize HepG2 cells to the apoptotic action of the drug. (c) 2005 Elsevier Inc. All rights reserved.