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Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

AIM: Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely...

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Detalles Bibliográficos
Autores principales: Li, Li, Wang, Yubo, Peng, Tao, Zhang, Kejun, Lin, Caiyu, Han, Rui, Lu, Conghua, He, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085167/
https://www.ncbi.nlm.nih.gov/pubmed/27144340
http://dx.doi.org/10.18632/oncotarget.9120
Descripción
Sumario:AIM: Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling. RESULTS: The present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin. EXPERIMENTAL DESIGN: The effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay. CONCLUSIONS: Metformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival.