Effects of flavonoids on the ABCG2-mediated pharmacokinetics and pharmacodynamics of mitoxantrone
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Multi-drug resistance (MDR) remains a major obstacle for the development of successful cancer therapy. An important mechanism for MDR is the enhanced cellular efflux of anticancer agents due to overexpression of ATP-binding cassette (ABC) transporter proteins (i.e. efflux transporters) such as Breast Cancer Resistance Protein (BCRP). Despite the emphasis on the development of inhibitors/modulators of efflux transporters to reverse MDR, the development of BCRP inhibitors is still limited to in vitro studies. It has been reported that many flavonoids, the most prevalent group of plant polyphenols in fruits, vegetables and beverages, demonstrate potent BCRP inhibitory effects in vitro. The overall goal of this project is to investigate the role of flavonoids in BCRP-mediated MDR and in the disposition of anticancer agents in vivo. The model cancer used in this project is breast cancer and mitoxantrone is selected as the model anticancer drug. We first evaluated the effect of single and multiple flavonoids on the accumulation and cytotoxicity of mitoxantrone in BCRP-overexpressing breast cancer cells and on the transport of mitoxantrone in BCRP-expressing normal cells. Based on our in vitro results, a few flavonoid candidates were further investigated in vivo. For the flavonoid 5,7-dimethoxyflavone (5,7-DMF), we have evaluated its chemosensitizing effect on BCRP-mediated mitoxantrone resistance in a xenograft breast tumor model and its impact on the PK and tissue distribution of mitoxantrone in mice. We also evaluated the inhibitory mechanism of the flavonoids biochanin A and kaempferol on BCRP. A high performance liquid chromatography (HPLC) was established and validated for mitoxantrone quantification. Additionally, we constructed a physiologically-based pharmacokinetic model for mitoxantrone to characterize its plasma and tissue distribution. We report for the first time that flavonoids influence the transport of mitoxantrone in BCRP-overexpressing normal cells and impact its PK and tissue distribution in vivo. The area under the plasma concentration-time curve (AUC) values of MX in several tissues, especially liver and kidney, were significantly increased when MX was co-administered with the single flavonoid 5,7-DMF and multiple flavonoids. We also show that 5,7-DMF can reverse BCRP-mediated mitoxantrone resistance in vivo in a xenograft study. We report for the first time that kaempferol is a BCRP substrate and therefore it may inhibit BCRP-mediated mitoxantrone efflux through competitive inhibition. Our results may have important clinical implications for tumors expressing BCRP and for those anticancer drugs which are substrates of BCRP. Since tested flavonoids are naturally occurring products, the results of our studies may be easily translated into clinical studies.