Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth.
Am J Pathol
; 178(1): 336-44, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-21224070
ABSTRACT
The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Morfolinas
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Cromonas
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Carcinoma Neuroendócrino
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Sirolimo
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Inibidores de Proteínas Quinases
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Serina-Treonina Quinases TOR
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Inibidores de Fosfoinositídeo-3 Quinase
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Neoplasias Intestinais
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Antibióticos Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article