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Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)2, in Reversing Multidrug Resistance Mediated
Tsz Cheung Chong1, Iris L K Wong1, Jiahua Cui1,2
1Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China.
Abstract:
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 Ac15(Az8) was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC50 for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that Ac15(Az8) 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 Ac15(Az8) resulted in plasma concentration above its EC50 (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 Ac15(Az8) is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.
Insights
A novel compound, Ac15(Az8), effectively inhibits breast cancer resistance transporter (BCRP) and reverses chemotherapy resistance in preclinical models. This potent and non-toxic BCRP inhibitor shows promise for combination cancer therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Overexpression of breast cancer resistance transporter (BCRP/ABCG2) contributes to chemotherapy failure in various cancers.
- Inhibiting BCRP's transport activity is a strategy to overcome multidrug resistance.
- Developing potent and selective BCRP inhibitors is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To identify and characterize a novel, potent, and non-toxic inhibitor of breast cancer resistance transporter (BCRP).
- To evaluate the efficacy of the identified inhibitor, Ac15(Az8), in reversing BCRP-mediated drug resistance in vitro and in vivo.
- To investigate the potential of Ac15(Az8) as a chemosensitizer in combination therapy for BCRP-overexpressing cancers.
Main Methods:
- Identification of Ac15(Az8) as a triazole-bridged flavonoid dimer with BCRP inhibitory activity.
- In vitro assessment of Ac15(Az8)'s efficacy in reversing topotecan resistance in BCRP-overexpressing cell lines (MCF7/MX100, S1M180).
- Mechanistic studies involving BCRP-ATPase activity, drug accumulation, and pharmacokinetic profiling.
- In vivo evaluation using a BCRP-overexpressing S1M180 xenograft model in Balb/c nude mice.
Main Results:
- Ac15(Az8) demonstrated potent inhibition of BCRP with low EC50 values (3 nM and 72 nM) in reversing topotecan resistance.
- Ac15(Az8) restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux without affecting BCRP levels.
- Pharmacokinetic studies showed sustained plasma concentrations of Ac15(Az8) above its EC50, increasing topotecan's AUC by 2-fold.
- In vivo studies showed Ac15(Az8) reversed BCRP-mediated resistance, inhibited tumor growth by 40%, and increased topotecan levels in xenografts.
Conclusions:
- Ac15(Az8) is a potent, non-toxic, and selective BCRP inhibitor with significant potential to reverse multidrug resistance.
- Ac15(Az8) acts by inhibiting BCRP-ATPase activity and drug efflux, not by down-regulating BCRP expression.
- Ac15(Az8) demonstrates promising preclinical efficacy in both in vitro and in vivo models, supporting its further investigation for combination cancer therapy.
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