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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/21/13261 |
| Summary: | 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 |