Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2)
Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer <b&g...
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2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| author | Tsz Cheung Chong Iris L. K. Wong Jiahua Cui Man Chun Law Xuezhen Zhu Xuesen Hu Jason W. Y. Kan Clare S. W. Yan Tak Hang Chan Larry M. C. Chow |
| author_facet | Tsz Cheung Chong Iris L. K. Wong Jiahua Cui Man Chun Law Xuezhen Zhu Xuesen Hu Jason W. Y. Kan Clare S. W. Yan Tak Hang Chan Larry M. C. Chow |
| author_sort | Tsz Cheung Chong |
| collection | DOAJ |
| description | Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer <b>Ac15(Az8)<sub>2</sub></b> was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC<sub>50</sub> for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that <b>Ac15(Az8)<sub>2</sub></b> restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg of <b>Ac15(Az8)<sub>2</sub></b> resulted in plasma concentration above its EC<sub>50</sub> (72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest that <b>Ac15(Az8)<sub>2</sub></b> is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:00:54Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b470e512a9744189a7e3f58b7d2ec6a02023-11-24T05:05:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211326110.3390/ijms232113261Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2)Tsz Cheung Chong0Iris L. K. Wong1Jiahua Cui2Man Chun Law3Xuezhen Zhu4Xuesen Hu5Jason W. Y. Kan6Clare S. W. Yan7Tak Hang Chan8Larry M. C. Chow9Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaDepartment of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, ChinaOverexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer <b>Ac15(Az8)<sub>2</sub></b> was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC<sub>50</sub> for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that <b>Ac15(Az8)<sub>2</sub></b> restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg of <b>Ac15(Az8)<sub>2</sub></b> resulted in plasma concentration above its EC<sub>50</sub> (72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest that <b>Ac15(Az8)<sub>2</sub></b> is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.https://www.mdpi.com/1422-0067/23/21/13261multidrug resistancebreast cancer resistance proteinBCRPABCG2flavonoid dimers |
| spellingShingle | Tsz Cheung Chong Iris L. K. Wong Jiahua Cui Man Chun Law Xuezhen Zhu Xuesen Hu Jason W. Y. Kan Clare S. W. Yan Tak Hang Chan Larry M. C. Chow Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) International Journal of Molecular Sciences multidrug resistance breast cancer resistance protein BCRP ABCG2 flavonoid dimers |
| title | Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) |
| title_full | Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) |
| title_fullStr | Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) |
| title_full_unstemmed | Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) |
| title_short | Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)<sub>2</sub>, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2) |
| title_sort | characterization of a potent selective and safe inhibitor ac15 az8 sub 2 sub in reversing multidrug resistance mediated by breast cancer resistance protein bcrp abcg2 |
| topic | multidrug resistance breast cancer resistance protein BCRP ABCG2 flavonoid dimers |
| url | https://www.mdpi.com/1422-0067/23/21/13261 |
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