Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
| Autor: | I-Ting Wu, Shih-Ya Huang, Bo-Hau Huang, Yu-Ning Teng, Tian Shung Wu, Chin-Chuan Hung, Tsui-Er Lee |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B ATPase Antineoplastic Agents Apoptosis ATP-binding cassette transporter RM1-950 P-glycoprotein ATPase binding Pharmacology Rhodamine 123 Lignans Natural product chemistry.chemical_compound Cell Line Tumor Cancer multi-drug resistance medicine Humans Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors Cytotoxicity ATP-binding cassette Adenosine Triphosphatases Antibiotics Antineoplastic Binding Sites biology Chemistry Cell Cycle Guaiacol Cinnamomum philippinense Drug Synergism General Medicine Drug Resistance Multiple Molecular Docking Simulation Cinnamophilin Verapamil Drug Resistance Neoplasm biology.protein Therapeutics. Pharmacology Efflux medicine.drug |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 144, Iss, Pp 112379-(2021) |
| ISSN: | 0753-3322 |
| DOI: | 10.1016/j.biopha.2021.112379 |
| Popis: | Cancer multi-drug resistance (MDR) caused by P-glycoprotein (P-gp) efflux is a critical unresolved clinical concern. The present study analyzed the effect of cinnamophilin on P-gp inhibition and MDR reversion. The effect of cinnamophilin on P-gp was investigated through drug efflux assay, ATPase assay, MDR1 shift assay, and molecular docking. The cancer MDR-reversing ability and mechanisms were analyzed through cytotoxicity and combination index (CI), cell cycle, and apoptosis experiments. P-gp efflux function was significantly inhibited by cinnamophilin without influencing the drug’s expression or conformation. Cinnamophilin uncompetitively inhibited the efflux of doxorubicin and rhodamine 123 and exhibited a distinct binding behavior compared with verapamil, the P-gp standard inhibitor. The half maximal inhibitory concentration of cinnamophilin for doxorubicin and rhodamine 123 efflux was 12.47 and 11.59 μM, respectively. In regard to P-gp energy consumption, verapamil-stimulated ATPase activity was further enhanced by cinnamophilin at concentrations of 0.1, 1, 10, and 20 μM. In terms of MDR reversion, cinnamophilin demonstrated synergistic cytotoxic effects when combined with docetaxel, vincristine, or paclitaxel. The CI was |
| Databáze: | OpenAIRE |
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