Effects of Single and Multiple Flavonoids on BCRP-Mediated Accumulation, Cytotoxicity and Transport of Mitoxantrone In Vitro

Abstract

The results indicate that flavonoids are potent BCRP inhibitors and that they exert additive effects when used in combination. Flavonoids demonstrate MDR-reversing effects, but also may influence the disposition of mitoxantrone and cause pharmacokinetic interactions.

Influence of overexpression of efflux proteins on the function and gene expression of endogenous peptide transporters in MDR-transfected MDCKII cell lines

“…MDCK cells express endogenous canine peptide transporters on both apical and basolateral membranes, whereas all the transfected exogenous efflux genes are expressed apically (Tang et al, 2002a,b; An and Morris, 2010). Fig.…”

Polyphenols Counteract Tumor Cell Chemoresistance Conferred by Multidrug Resistance Proteins

“…Also An & Morris [77] have demonstrated recently the additive effect of flavonoids applied in combination of 2-10 compounds on mitoxantrone accumulation and cytotoxicity in BCRPoverexpressing MCF-7 MX100 cell line. Kaempferide, biochanin A, 5,7-dimethoxyflavone, and 8-methylflavone also applied alone effectively increased the cytotoxicity of mitoxantrone in the human breast cancer MCF-7 MX100 cells and inhibited mitoxantrone transport across MDCK cell monolayers.…”

Quantification of 5,7-dimethoxyflavone in mouse plasma using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and its application to a pharmacokinetic study

“…Breast Cancer Resistance Protein (BCRP) is one of the main efflux transporters associated with MDR. 5,7-DMF has been reported to be a potent inhibitor of BCRP, with an IC50 of 2.5 M (equivalent to 0.703 g/mL) [6][7][8]. 5,7-DMF can significantly increase the accumulation of mitoxatrone (an anticancer agent) in BCRPoverexpressed breast cancer cells and correspondingly enhanced the cytotoxicity of mitoxatrone in those cells at nano-molar to low micro-molar concentration range.…”

“…In addition, 5,7-DMF has also been reported to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human leukemic cells and human hepatocellular carcinoma cells [4,5]. Very recently, 5,7-DMF was reported to have potent inhibitory effect on efflux transporter Breast Cancer Resistance Protein (BCRP) [6][7][8], a type of transporter that is known to be present in various cancer cells and play an important roles in multi-drug resistance [9]. Therefore, 5,7-DMF may represent a very promising chemosensitizing agent to reverse the efflux transporter-mediated multi-drug resistance.…”