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.

DI BARTOLOMEO, S., Spinedi, A. (2005). Two glucosylceramide synthase inhibitors attenuate doxorubicin-induced p21Cip1/Waf1 upregulation in HepG2 cells, irrespective of their differential chemosensitizing properties, 330(1), 242-246 [10.1016/j.bbrc.2005.02.160].

Two glucosylceramide synthase inhibitors attenuate doxorubicin-induced p21Cip1/Waf1 upregulation in HepG2 cells, irrespective of their differential chemosensitizing properties

DI BARTOLOMEO, SABRINA;SPINEDI, ANGELO
2005-01-01

Abstract

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.
2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/09 - FISIOLOGIA
English
Con Impact Factor ISI
Apoptosis; Doxorubicin; Glucosylceramide synthase inhibitor; Hepatocarcinoma; p21Cip1/Waf1; p53
DI BARTOLOMEO, S., Spinedi, A. (2005). Two glucosylceramide synthase inhibitors attenuate doxorubicin-induced p21Cip1/Waf1 upregulation in HepG2 cells, irrespective of their differential chemosensitizing properties, 330(1), 242-246 [10.1016/j.bbrc.2005.02.160].
DI BARTOLOMEO, S; Spinedi, A
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/41051
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 1
social impact