| Autor: |
Chong TC; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Wong ILK; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Cui J; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China.; School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China., Law MC; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Zhu X; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Hu X; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Kan JWY; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Yan CSW; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China., Chan TH; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China.; Department of Chemistry, McGill University, Montreal, QC H3A 2K6, Canada., Chow LMC; Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China. |
| Abstrakt: |
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) 2 was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC 50 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) 2 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) 2 resulted in plasma concentration above its EC 50 (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) 2 is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers. |
