Mammalian target of rapamycin inhibition as therapy for hematologic malignancies.
Cancer
; 100(4): 657-66, 2004 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-14770419
ABSTRACT
The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Regulação Neoplásica da Expressão Gênica
/
Neoplasias Hematológicas
/
Sirolimo
Limite:
Humans
Idioma:
En
Revista:
Cancer
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos