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Foretinib, a c-MET receptor tyrosine kinase inhibitor, tackles multidrug resistance in cancer cells by inhibiting ABCB1 and ABCG2 transporters
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Fatemeh Moosavi   , Somayeh Nazari , Fatemeh Mosaffa , Omidreza Firuzi |
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Abstract: (237 Views) |
Introduction: Multidrug resistance (MDR) remains a major obstacle to pharmacological treatment in cancer. Overexpression of ATP-binding cassette (ABC) transporters, including ABCB1 or ABCG2, is an important MDR mechanism encountered in many cancer types. Foretinib, a multitargeted TKI, is currently being evaluated in clinical trials. The present study was designed to evaluate for the first time whether foretinib can circumvent ABCB1 and ABCG2-mediated MDR in treatment-resistant cancer models.
Methods and Materials: The accumulation of fluorescent substrates in MES-SA/DX5 cells with high expression of ABCB1 and MCF-7/MX with high expression of ABCG2 and their parent cells was investigated by flow cytometry. The inhibitory activity of cancer cell growth by fortinib and chemotherapy drugs alone and in combination with resistant cells was evaluated by the MTT method. Analysis of the combined effects of drugs was done with CalcuSyn software.
Results: First, it was shown that fortinib increases the intracellular accumulation of rhodamine 123 (Rho 123) and mitoxantrone in MES SA/DX5 and MCF-7/MX cancer cells with accumulation ratios of 12 and 2.2 μM, respectively, at a concentration of 25 μK. In addition, our findings also showed that fortinib inhibited the cytotoxic effects of chemotherapy drugs, doxorubicin and mitoxantrone with combination index values of 0.64±0.08 and 0.47±0.09, respectively, in resistant MES-SA/DX5 cancer cells, and MCF7/MX synergistically improve Computational analysis also suggested that the main target site for fortinib is the drug binding region of ABCB1 and ABCG2 transporters.
Conclusion: Overall, our results suggest that foretinib can target MDR-linked ABCB1 and ABCG2 transporters in clinical cancer therapy.
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| Keywords: Tyrosine kinase inhibitors, drug resistance, MDR reversal, P-glycoprotein, breast cancer resistance protein |
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Full-Text [PDF 327 kb]
(35 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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