c-MET tyrosine kinase inhibitors reverse multidrug resistance in breast cancer cells by targeting ABCG2 transporter.

Abstract

Background: Overcoming multidrug resistance (MDR), which is often caused by the overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a major challenge for cancer treatment. Receptor tyrosine kinase inhibitors have demonstrated potential in reversing MDR. This study aimed to investigate the effects of c-MET RTKIs on the reversal of MDR induced by ABCG2 in breast cancer cells.

Methods: MTT assay was employed to assess antiproliferative activity of c-MET inhibitors, including cabozantinib, crizotinib, and PHA665752. The accumulation of the fluorescent probe mitoxantrone was evaluated by flow cytometry. The drug-drug interaction in combination treatments was analyzed using CalcuSyn software.

Results: The combination of cabozantinib, crizotinib, and PHA665752 with mitoxantrone resulted in synergistic effects in MDR cells. This was demonstrated by the mean CI values of 0.32 ± 0.07, 0.53 ± 0.05, and 0.59 ± 0.03, respectively. In the same cells, c-MET inhibitors enhanced the accumulation of mitoxantrone, with accumulation ratios ranging from 1.6 to 3.8, while no change was found in parental MCF-7 cells. Computational analysis revealed that the drug-binding region of ABCG2 transporters could be a viable target for these compounds.

Conclusion: c-MET inhibitors hold potential as effective agents for reversing MDR in ABCG2-medicated drug-resistant cancer cells.