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Met receptor tyrosine kinase inhibitors reverse anticancer drug resistance in ABCB1 and ABCG2 overexpressing cells
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Omidreza Firuzi   , Somayeh Nazari , Fatemeh Moosavi , Fatemeh Mosaffa |
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Abstract: (232 Views) |
Introduction: Multidrug resistance (MDR), which is usually mediated through the overexpression of ATP-binding cassette (ABC) transporters, including ABCB1 and ABCG2, is an important factor in chemotherapy failure. It has been reported that some anticancer tyrosine kinase inhibitors (TKIs) can reverse ABC transporter-mediated MDR. The purpose of this study was to investigate the effects of cabozantinib, crizotinib, and PHA665752 as MET TKIs on the reversal of MDR induced by ABCB1 or ABCG2 in vitro.
Methods and Materials: ABCB1-overexpressing MES-SA/DX5 and ABCG2-overexpressing MCF-7/MX and their parenteral cells were used as MDR cell models. Accumulation of fluorescent probes, Rhodamine 123 and mitoxantrone, in MES-SA/DX5 and MCF-7/MX, respectively, and their parenteral cells was assessed by flow cytometry. The growth inhibitory activity of MET inhibitors including cabozantinib, crizotinib, and PHA665752 as monotherapies and also in combination with chemotherapeutic drugs were evaluated by MTT assay. CalcuSyn software was used to analyze the drug-drug interaction in combination treatments.
Results: First, it was observed that cabozantinib, crizotinib, and PHA665752 increase the intracellular accumulation of Rhodamine 123 with accumulation ratios of 17.8, 7.9, and 11.6 in MES SA/DX5 cancer cells and 3.8 and 1.6 in ABCG2 high expression cancer cells. Furthermore, our findings also showed that cabozantinib, crizotinib, and PHA665752 synergistically enhanced the cytotoxic effects of the chemotherapy drug doxorubicin with CI values of 0.54 ± 0.08 and 0.69 ± 0.1 in MCF7/MX MES-SA/DX5 and MCF7/MX cells, respectively.
Conclusion: Overall, our results suggest that MET inhibitors can serve as promising MDR reversal agents in ABCB1- and ABCG2-medicated drug-resistant cancer cells.
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| Keywords: Tyrosine kinase inhibitors, ATP-binding cassette (ABC) transporter, drug resistance, P-glycoprotein, breast cancer resistance protein |
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Full-Text [PDF 344 kb]
(28 Downloads)
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Type of Study: Research |
Subject:
General
Received: 2024/01/28 | Accepted: 2023/08/1 | Published: 2023/08/1
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