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Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents

Authors Ayoub NM, Al-Shami KM, Alqudah MA, Mhaidat NM

Received 8 August 2017

Accepted for publication 7 September 2017

Published 5 October 2017 Volume 2017:10 Pages 4869—4883

DOI https://doi.org/10.2147/OTT.S148604

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Yao Dai

Nehad M Ayoub, Kamal M Al-Shami, Mohammad A Alqudah, Nizar M Mhaidat

Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Abstract:
MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. In vitro wound-healing assay was used to examine the effect of crizotinib on breast cancer cell migration. The expressions of Ki-67, MET, and phospho-MET receptors were characterized using immunofluorescence staining. Results showed that crizotinib has significant anti-proliferative activity on all mammary tumor cells with IC50 values of 5.16, 1.5, and 3.85 µM in MDA-MB-231, MCF-7, and SK-BR-3 cells, respectively. Crizotinib induced cytotoxic effects in all breast cancer cells examined. Combined treatment of small dose of crizotinib with paclitaxel or doxorubicin exhibited a highly synergistic inhibition of growth of MDA-MB-231 and MCF-7 cells with combination index values <1 while no significant effect was observed in SK-BR-3 cells compared with individual compounds. Treatment with crizotinib demonstrated a remarkable reduction in the expression of Ki-67 protein in all 3 tested cell lines. Crizotinib inhibited migration and invasion of MDA-MB-231 cells in a dose-dependent fashion. Crizotinib reduced MET receptor activation in MDA-MB-231 cells when treated at effective concentrations. In conclusion, crizotinib suppressed proliferation, migration, and invasion of breast cancer cells in vitro. The results of this study demonstrated that combined treatment of crizotinib with chemotherapeutic agents resulted in a synergistic growth inhibition of specific breast cancer cell lines.

Keywords: crizotinib, breast cancer, MET receptor, chemotherapy, migration, invasion

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