Osimertinib (AZD9291), a Mutant-Selective EGFR Inhibitor, Reverses ABCB1-Mediated Drug Resistance in Cancer Cells
| Autor: | Leli Zeng, Dong-Hua Yang, Zhe-Sheng Chen, Yi-Jun Wang, Xiao-Yu Zhang, Pranav Gupta, Yun-Kai Zhang, Xiu-Qi Wang, Megan Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
ATP Binding Cassette Transporter Subfamily B osimertinib multidrug resistance ABCB1 tyrosine kinase inhibitors Pharmaceutical Science Biology Pharmacology Piperazines Article Analytical Chemistry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine lcsh:Organic chemistry Cell Line Tumor Neoplasms Drug Discovery Humans Osimertinib Epidermal growth factor receptor Physical and Theoretical Chemistry EGFR inhibitors Acrylamides Aniline Compounds Organic Chemistry 3. Good health Multiple drug resistance ErbB Receptors 030104 developmental biology Paclitaxel chemistry Chemistry (miscellaneous) Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Mutation biology.protein Molecular Medicine Efflux Tyrosine kinase |
| Zdroj: | Molecules; Volume 21; Issue 9; Pages: 1236 Molecules Molecules, Vol 21, Iss 9, p 1236 (2016) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules21091236 |
| Popis: | In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers. |
| Databáze: | OpenAIRE |
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