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

Li Li; Yubo Wang; Tao Peng; Kejun Zhang; Caiyu Lin; Rui Han; Conghua Lu; Yong He

doi:10.18632/oncotarget.9120

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Research Papers:

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

Li Li, Yubo Wang, Tao Peng, Kejun Zhang, Caiyu Lin, Rui Han, Conghua Lu and Yong He _

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Oncotarget. 2016; 7:34442-34452. https://doi.org/10.18632/oncotarget.9120

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Abstract

Li Li1,*, Yubo Wang1,*, Tao Peng1,*, Kejun Zhang2, Caiyu Lin1, Rui Han1, Conghua Lu1, Yong He1

1Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China

2Department of Clinical Labratory, Daping Hospital, Third Military Medical University, Chongqing 400042, China

*These authors contributed equally to this work

Correspondence to:

Yong He, email: [email protected]

Keywords: metformin, crizotinib, IGF-1R, lung cancer, resistance

Received: November 01, 2015 Accepted: March 31, 2016 Published: April 30, 2016

ABSTRACT

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.

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Research Papers:

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

Abstract