Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions
Abstract Breast cancer resistance protein (BCRP), a member of the ATP-binding cassette transporter family, plays a key role in the efflux of various drugs and is linked to multidrug resistance in cancer therapy. Flavonoids, particularly those with a flavonol backbone, have shown promise as inhibitor...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-13908-1 |
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| author | Kyeong-Ryoon Lee Min-Ji Kang Min Ju Kim Yiseul Im Hyeon-Cheol Jeong Yoon-Jee Chae |
| author_facet | Kyeong-Ryoon Lee Min-Ji Kang Min Ju Kim Yiseul Im Hyeon-Cheol Jeong Yoon-Jee Chae |
| author_sort | Kyeong-Ryoon Lee |
| collection | DOAJ |
| description | Abstract Breast cancer resistance protein (BCRP), a member of the ATP-binding cassette transporter family, plays a key role in the efflux of various drugs and is linked to multidrug resistance in cancer therapy. Flavonoids, particularly those with a flavonol backbone, have shown promise as inhibitors of BCRP activity; however, their specific inhibitory effects are not fully understood. This study explored the inhibitory effects of 77 flavonols on BCRP and identified 22 compounds with significant inhibitory activity. Among them, 14 flavonols had half-maximal inhibitory concentrations (IC50) values below 5 µM, effectively reversing BCRP-mediated resistance to SN-38 in vitro. Molecular docking analysis revealed key interactions between flavonols and BCRP, including π-stacking, hydrogen bonding, and hydrophobic interactions. Structural modifications, including hydroxylation and methylation, enhanced the binding affinity of the flavonols. In vivo studies with 3,4′-dimethoxyflavone and 3,6,3′,4′-tetramethoxyflavone resulted in increased systemic exposure to sulfasalazine, a known BCRP substrate. These findings provide mechanistic insights into flavonol-BCRP interactions, suggesting their potential to enhance drug exposure and efficacy. Future research should focus on clinical applications to explore the therapeutic potential of these flavonols for improved drug responses. |
| format | Article |
| id | doaj-art-109d6fe204fb48ab85c2f9331b81a0de |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-109d6fe204fb48ab85c2f9331b81a0de2025-08-20T03:04:25ZengNature PortfolioScientific Reports2045-23222025-08-0115111310.1038/s41598-025-13908-1Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactionsKyeong-Ryoon Lee0Min-Ji Kang1Min Ju Kim2Yiseul Im3Hyeon-Cheol Jeong4Yoon-Jee Chae5Laboratory Animal Resource Center, Korea Research Institute of Bioscience and BiotechnologyCollege of Pharmacy, Woosuk UniversityLaboratory Animal Resource Center, Korea Research Institute of Bioscience and BiotechnologyLaboratory Animal Resource Center, Korea Research Institute of Bioscience and BiotechnologyLaboratory Animal Resource Center, Korea Research Institute of Bioscience and BiotechnologyCollege of Pharmacy, Woosuk UniversityAbstract Breast cancer resistance protein (BCRP), a member of the ATP-binding cassette transporter family, plays a key role in the efflux of various drugs and is linked to multidrug resistance in cancer therapy. Flavonoids, particularly those with a flavonol backbone, have shown promise as inhibitors of BCRP activity; however, their specific inhibitory effects are not fully understood. This study explored the inhibitory effects of 77 flavonols on BCRP and identified 22 compounds with significant inhibitory activity. Among them, 14 flavonols had half-maximal inhibitory concentrations (IC50) values below 5 µM, effectively reversing BCRP-mediated resistance to SN-38 in vitro. Molecular docking analysis revealed key interactions between flavonols and BCRP, including π-stacking, hydrogen bonding, and hydrophobic interactions. Structural modifications, including hydroxylation and methylation, enhanced the binding affinity of the flavonols. In vivo studies with 3,4′-dimethoxyflavone and 3,6,3′,4′-tetramethoxyflavone resulted in increased systemic exposure to sulfasalazine, a known BCRP substrate. These findings provide mechanistic insights into flavonol-BCRP interactions, suggesting their potential to enhance drug exposure and efficacy. Future research should focus on clinical applications to explore the therapeutic potential of these flavonols for improved drug responses.https://doi.org/10.1038/s41598-025-13908-1Breast cancer resistance proteinFlavonolsDrug interactionsDrug resistanceSN-38 |
| spellingShingle | Kyeong-Ryoon Lee Min-Ji Kang Min Ju Kim Yiseul Im Hyeon-Cheol Jeong Yoon-Jee Chae Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions Scientific Reports Breast cancer resistance protein Flavonols Drug interactions Drug resistance SN-38 |
| title | Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions |
| title_full | Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions |
| title_fullStr | Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions |
| title_full_unstemmed | Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions |
| title_short | Inhibition of breast cancer resistance protein by flavonols: in vitro, in vivo, and in silico implications of the interactions |
| title_sort | inhibition of breast cancer resistance protein by flavonols in vitro in vivo and in silico implications of the interactions |
| topic | Breast cancer resistance protein Flavonols Drug interactions Drug resistance SN-38 |
| url | https://doi.org/10.1038/s41598-025-13908-1 |
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