Characterization of novel flavonoid dimers as breast cancer resistance protein (BCRP)-modulators

Abstract

Cancer causes many deaths each year. A lot of anticancer drugs have been developed and some of them give promising results. Nevertheless, some patients become unresponsive to chemotherapy after prolonged treatment and develop multidrug resistance (MDR). Some MDR cases are caused by overexpression of ATP Binding Cassette (ABC) transporter ABCG2/BCRP. Inhibition of BCRP-mediated drug efflux could be one of the possible solutions to tackle MDR. Previously, flavonoid dimers have been shown to reverse ABCB1-mediated drug resistance. In view of the promising reversal potential of flavonoid dimers, a click chemistry approach was developed to generate a library of novel flavonoid dimers to discover new BCRP modulators. Click chemistry allowed rapid synthesis of a large combinations of triazole-containing homodimers and heterodimers of flavonoids. Screening resulted in the identification of FD 15_8 as a potent BCRP modulator. Its EC50s were 1.3±0.7nM in reversing topotecan resistance in BCRP-overexpressing MCF7/MX100 cells and 70.4±17.1nM in S1M180 cells. FD 15_8 increased intracellular level of topotecan and doxorubicin in BCRP-expressing cells. It did not affect BCRP protein expression level, nor cellular localization of BCRP. Instead FD15_8 inhibited BCRP-ATPase activity. Lineweaver-Burk and Dixon analysis suggested that FD 15_8 was a non-competitive inhibitor for BCRP in a mixed mode of inhibition. Intraperitoneal administration of FD 15_8 resulted in the best pharmacokinetics profile in mice with plasma level maintained above its EC₅₀ level for more than 10 hours. Co-administration of FD 15_8 at 45 mg/kg with topotecan at 2 mg/kg can suppress the S1M180 tumor volume by 40.3% after 24 times of treatment for once every two days. Administration FD 15_8 alone or topotecan did not result in severe toxicity. No death incidence recorded during the combination of 45 mg/kg FD 15_8 and 2mg/kg topotecan combination group. In conclusion, FD 15_8 is a safe and potent BCRP modulator.