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

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.

• Authors: Li Li, Yubo Wang, Tao Peng, Kejun Zhang, Caiyu Lin, Rui Han, Conghua Lu, Yong He
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 23 Pg. 34442-52 (Jun 07 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27144340 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• IGF1R protein, human
• Pyrazoles
• Pyridines
• Receptors, Somatomedin
• Crizotinib
• Metformin
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases
• Receptor, IGF Type 1

Topics

• Anaplastic Lymphoma Kinase
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crizotinib
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Metformin (pharmacology)
• Neoplasm Invasiveness (pathology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Receptor, IGF Type 1
• Receptors, Somatomedin (antagonists & inhibitors)
• Signal Transduction (drug effects)