Biomedical subjects

Xinning Yang

Publications and source records attributed to Xinning Yang.

4 recordsLinked to original sources

PubMed2005

Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein.

Breast cancer resistance protein (BCRP) is a newly identified ABC transporter, which plays an important role in drug disposition and represents an additional mechanism for the development of MDR. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be BCRP inhibitors. The objective of the present study was to elucidate the SAR and derive a QSAR model for flavonoid-BCRP interaction. The EC(50) values for increasing mitoxantrone accumulation in MCF-7 MX100 cells for 25 flavonoids, from five flavonoid subclasses, were determined in this study or obtained from our previous publication [Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res 2004;21(7):1263-73], and ranged from 0.07+/-0.02 microM to 183+/-21.7 microM. We found that the presence of a 2,3-double bond in ring C, ring B attached at position 2, hydroxylation at position 5, lack of hydroxylation at position 3 and hydrophobic substitution at positions 6, 7, 8 or 4', are important structural properties important for potent flavonoid-BCRP interaction. These structural requirements are similar but not identical to those for potent flavonoid-NBD2 (P-glycoprotein) interaction, indicating that inhibition of BCRP by flavonoids may involve, in part, the binding of flavonoids with the NBD of BCRP. In addition, a QSAR model consisting three structural descriptors was constructed, and both internally and externally validated, suggesting the model could be used to quantitatively predict BCRP inhibition activity of flavonoids. These findings should be useful for predicting BCRP inhibition activity of other untested flavonoids and for guiding the synthesis of potent BCRP inhibitors for potential clinical application.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Effects of dihydropyridines and pyridines on multidrug resistance mediated by breast cancer resistance protein: in vitro and in vivo studies.

Breast cancer resistance protein (BCRP, ABCG2) is a recently identified member of the ATP-binding cassette family of cell surface transport proteins. This study was conducted to investigate the effect of a series of newly synthesized 1,4-dihydropyridines and pyridines, designed as potent P-glycoprotein inhibitors, on BCRP-mediated drug efflux both in vitro and in vivo. The effects of 25 synthesized dihydropyridines and corresponding pyridines along with 4 commercially available dihydropyridines (niguldipine, nicardipine, nifedipine, and nitrendipine) on the intracellular accumulation of the BCRP substrate mitoxantrone were evaluated in BCRP-expressing human breast cancer MCF-7/MX100 and human non-small cell lung cancer H460/MX20 cells. At a 2.5 microM concentration, 24 of 25 newly synthesized dihydropyridines and pyridines produced a significant increase of mitoxantrone accumulation in both cell lines. The most potent compound was able to enhance mitoxantrone accumulation approximately 4.5-fold, greater than that obtained with 10 microM fumitremorgin C, which is a specific BCRP inhibitor. The results from the two cell lines showed good correlation (r(2) = 0.71, p < 0.01). Niguldipine, nicardipine, and nitrendipine also demonstrated potent BCRP inhibition, whereas nifedipine had no effect. The effects of the dihydropyridine and pyridine compounds on mitoxantrone cytotoxicity paralleled their effects on mitoxantrone accumulation. Coadministration of a selected dihydropyridine compound, I(m) [DHP-014; 3-(3-(4,4-diphenylpiperidin-1-yl)propyl) 5-methyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate)] with topotecan, a good BCRP substrate and a moderate to poor P-glycoprotein substrate, resulted in significant increases in the systemic exposure and peak concentration of topotecan in Sprague-Dawley rats when oral topotecan (2 mg/kg) was combined with 20 mg/kg DHP-014. The observed increase of topotecan exposure provides proof-of-concept for in vivo inhibition of BCRP by these agents.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport.

PURPOSE: The purpose of this study was to determine the dynamic parameter (EC50) of flavonoids apigenin, biochanin A, chrysin, genistein, kaempferol, hesperetin, naringenin, and silymarin for breast cancer resistance protein (BCRP) inhibition when used alone, and to evaluate their potential interactions (additive, synergistic, or antagonistic) with regards to BCRP inhibition when used in multiple-flavonoid combinations. METHODS: The effects of flavonoids on BCRP-mediated transport were examined by evaluating their effects on mitoxantrone accumulation and cytotoxicity in MCF-7 MX100 cells overexpressing BCRP. The EC50 values of these flavonoids for increasing mitoxantrone accumulation were estimated using a Hill equation. The potential interactions among multiple flavonoids with regard to BCRP inhibition were assessed by isobologram and Berenbaum's interaction index methods. RESULTS: The EC50 values of these flavonoids for increasing mitoxantrone accumulation ranged from 0.39+/-0.13 microM to 33.7+/-2.78 microM. Quantitative analysis of the combined effects of multiple flavonoids on mitoxantrone accumulation indicated that these flavonoids act additively in inhibiting BCRP when given as 2-, 3-, 5-, or 8-flavonoid combinations with equimolar concentrations of all constituents. The results of the mitoxantrone cytotoxicity studies were consistent with these findings. CONCLUSIONS: The additive effects of multiple flavonoids for BCRP inhibition suggests that prediction of BCRP-mediated food (herbal product)-drug interactions should also take into consideration the presence of multiple flavonoids and provides a rationale for using "flavonoid cocktails" as a potential approach for multidrug resistance reversal in cancer treatment.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport.

Breast cancer resistance protein (BCRP) is a newly identified ATP-binding cassette transporter, shown to confer multidrug resistance (MDR) to a number of important anticancer agents and play an important function in governing drug disposition. Flavonoids are a class of polyphenolic compounds widely present in foods and herbal products. The interactions of flavonoids with P-glycoprotein and multidrug resistance-associated protein 1 have been reported; however, their interaction with BCRP is unknown. Our objective was to evaluate the effects of 20 naturally occurring flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone in both BCRP-overexpressing and BCRP-negative human cell lines. BCRP-overexpressing and BCRP-negative human breast cancer cells (MCF-7) and large cell lung carcinoma cells (NCI-H460) were used in these studies. Many of the tested flavonoids (50 microM) increased mitoxantrone accumulation in BCRP-overexpressing cells, completely reversing mitoxantrone resistance, with no effect on the corresponding BCRP-negative cells, indicating that these flavonoids are BCRP inhibitors. The effects of these flavonoids on the cellular accumulation and cytotoxicity of mitoxantrone were flavonoid concentration dependent, and significant changes were produced at concentrations lower than 10 microM for most of the flavonoids. Chrysin and biochanin A were the most potent BCRP inhibitors, producing significant increases in mitoxantrone accumulation at concentrations of 0.5 or 1.0 microM and in mitoxantrone cytotoxicity at a concentration of 2.5 microM. Flavonoid glycosides had no effects on the BCRP-mediated transport of mitoxantrone. The results obtained in this study could be clinically relevant in terms of both MDR reversal in cancer treatment and drug-flavonoid pharmacokinetic interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗