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Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.
Storozhuk, Y; Hopmans, S N; Sanli, T; Barron, C; Tsiani, E; Cutz, J-C; Pond, G; Wright, J; Singh, G; Tsakiridis, T.
Afiliación
  • Storozhuk Y; Department of Research, Juravinski Cancer Center, 699 Concession Street, Hamilton L8V 5C2, ON, Canada.
Br J Cancer ; 108(10): 2021-32, 2013 May 28.
Article en En | MEDLINE | ID: mdl-23632475
BACKGROUND: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). METHODS: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit(-/-) embryos (AMPKα1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). RESULTS: Metformin (2.5 µM-5 mM) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the Akt-mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2(-/-)-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR-4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. CONCLUSION: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fármacos Sensibilizantes a Radiaciones / Adenilato Quinasa / Proteínas Serina-Treonina Quinasas / Carcinoma de Pulmón de Células no Pequeñas / Proteínas de Ciclo Celular / Proteínas Supresoras de Tumor / Proliferación Celular / Proteínas de Unión al ADN / Neoplasias Pulmonares / Metformina Límite: Animals / Humans Idioma: En Revista: Br J Cancer Año: 2013 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fármacos Sensibilizantes a Radiaciones / Adenilato Quinasa / Proteínas Serina-Treonina Quinasas / Carcinoma de Pulmón de Células no Pequeñas / Proteínas de Ciclo Celular / Proteínas Supresoras de Tumor / Proliferación Celular / Proteínas de Unión al ADN / Neoplasias Pulmonares / Metformina Límite: Animals / Humans Idioma: En Revista: Br J Cancer Año: 2013 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido