title: Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Clinical Labratory, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Conghua
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D011720:Pyrazoles; D011725:Pyridines; D017451:Receptors, Somatomedin; D000077547:Crizotinib; D008687:Metformin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1
keywords: IGF-1R; crizotinib; lung cancer; metformin; resistance