Enhanced susceptibility to apoptosis of oral squamous cell carcinoma cells subjected to combined treatment with anticancer drugs and phosphatidylinositol 3-kinase inhibitors.
Int J Oncol
; 31(5): 1141-7, 2007 Nov.
Article
em En
| MEDLINE
| ID: mdl-17912441
ABSTRACT
The purpose of this study was to determine whether phosphatidylinositol 3-kinase (PI 3-K) inhibitors could modulate the apoptotic activity of the anticancer drugs cisplatin, 5-fluorouracil or docetaxel in an oral squamous cell carcinoma (OSCC) cell line, HSC-2. In preliminary experiments, cisplatin, 5-fluorouracil and docetaxel inhibited the proliferation of OSCC cells in a dose-dependent manner. We found that two PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt in OSCC cells. Treatment of OSCC cells with PI 3-K inhibitors significantly enhanced cisplatin-, 5-fluorouracil- or docetaxel-induced apoptosis. Caspase-3 and -9 inhibitors, but not a caspase-8 inhibitor, reduced anticancer drug-mediated apoptosis in PI 3-K inhibitor-treated OSCC cells, suggesting that the apoptotic pathway induced by the combination of anticancer drug therapy and PI 3-K inhibition may be functionally related to the intrinsic apoptotic pathway in OSCC cells. Expression of Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1), and X-linked IAP was down-regulated, and expression of Bax was up-regulated by PI 3-K inhibitors, while that of Bcl-xL, Bak and cIAP-2 was not attenuated. We also found that Bad phosphorylation was down-regulated by PI 3-K inhibitors. These results suggested that inhibition of PI 3-K enhances the susceptibility of OSCC cells to anticancer drug-mediated apoptosis through regulation of expression and post-translational modification of both pro- and anti-apoptotic proteins. These findings could potentially lead to new strategies for improving the efficacy of anticancer drugs in OSCC cells.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Bucais
/
Carcinoma de Células Escamosas
/
Apoptose
/
Inibidores de Proteínas Quinases
/
Inibidores de Fosfoinositídeo-3 Quinase
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article