Inhibition of the membrane translocation and activation of protein kinase C, and potentiation of doxorubicin-induced apoptosis of hepatocellular carcinoma cells by tamoxifen.
Biochem Pharmacol
; 55(4): 523-31, 1998 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-9514088
ABSTRACT
Hepatocellular carcinoma (HCC) is characterized by high drug resistance to currently available chemotherapeutic agents. In a prospective clinical study, we have demonstrated that high-dose tamoxifen significantly enhanced the therapeutic efficacy of doxorubicin in patients with far-advanced HCC. In a search for a possible mechanism, we found that tamoxifen at a clinically achievable concentration (2.5 microM) significantly enhanced doxorubicin-induced cytotoxicity and apoptosis of Hep-3B cells, a multidrug resistance (MDR)-1 expressing HCC cell line. This synergistic cytotoxic effect of tamoxifen, at this concentration, however, was not mediated by MDR inhibition. Instead, as evidenced by both western blot and immunofluorescence studies, tamoxifen inhibited the cytoplasmic-membrane translocation of protein kinase C (PKC)-alpha. 12-O-Tetradecanoylphorbol-13-acetate (TPA) restored the membrane translocation of PKC-alpha and abrogated the synergistic cytotoxicity of tamoxifen. We also showed that tamoxifen, at this concentration, did not directly affect the enzyme activity of PKC. Further, membrane translocation of other membrane-bound proteins, such as Ras protein, was similarly inhibited by tamoxifen, but could not be restored by the addition of TPA. Together, these data suggested that tamoxifen may act on the cytoplasmic membrane, and thereby inhibit PKC-alpha translocation to the membrane where it is activated. We hypothesize that high-dose tamoxifen may be an effective modulator of doxorubicin in the treatment of HCC, and suggest that biochemical modulation of PKC as a measure to improve systemic chemotherapy for HCC deserves further investigation.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Tamoxifeno
/
Proteína Quinase C
/
Doxorrubicina
/
Apoptose
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article