c-MET tyrosine kinase inhibitors reverse drug resistance mediated by the ATP-binding cassette transporter B1 (ABCB1) in cancer cells

This study investigated the potential of MET kinase inhibitors, cabozantinib, crizotinib, and PHA665752, in reversing multidrug resistance (MDR) mediated by ABCB1 in cancer cells. The accumulation of the fluorescent probe, Rhodamine 123, was assessed using flow cytometry and fluorescence microscopy...

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Bibliographic Details
Published in:3 Biotech 2025, Vol.15 (1), p.2
Main Authors: Nazari, Somayeh, Poustforoosh, Alireza, Paul, Priyanka Rani, Kukreti, Ritushree, Tavakkoli, Marjan, Saso, Luciano, Firuzi, Omidreza, Moosavi, Fatemeh
Format: Article
Language:English
Subjects:
Agriculture
Bioinformatics
Biomaterials
Biotechnology
Cancer Research
Chemistry
Chemistry and Materials Science
Original Article
Stem Cells
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Summary:This study investigated the potential of MET kinase inhibitors, cabozantinib, crizotinib, and PHA665752, in reversing multidrug resistance (MDR) mediated by ABCB1 in cancer cells. The accumulation of the fluorescent probe, Rhodamine 123, was assessed using flow cytometry and fluorescence microscopy in MDR MES-SA/DX5 and parental cells. The growth inhibitory activity of MET inhibitors as monotherapies and in combination with chemotherapeutic drugs was evaluated by MTT assay. CalcuSyn software was used to analyze the combination index (CI) as an index of drug-drug interaction in combination treatments. Results showed that at concentrations of 5, and 25 μM, c-MET inhibitors significantly increased Rhodamine 123 accumulation in MDR cells, with ratios up to 17.8 compared to control cells, while exhibiting no effect in parental cells. Additionally, the combination of c-MET inhibitors with the chemotherapeutic agent doxorubicin synergistically enhanced cytotoxicity in MDR cells, as evidenced by combination index (CI) values of 0.54 ± 0.08, 0.69 ± 0.1, and 0.85 ± 0.07 for cabozantinib, crizotinib, and PHA665752, respectively. While all three c-MET inhibitors stimulated ABCB1 ATPase activity in different manners at certain concentrations, PHA-665752 suppressed it at high concentration. In silico analysis also suggested that the transmembrane domains (TMD) of ABCB1 transporters could be considered potential target for these agents. Our results suggest that c-MET inhibitors can serve as promising MDR reversal agents in ABCB1-medicated drug-resistant cancer cells.
ISSN:2190-572X
2190-5738
DOI:10.1007/s13205-024-04162-9