Zhou Xiao-Fei, Yang Xinning, Wang Qi, Coburn Robert A, Morris Marilyn E
University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.
Drug Metab Dispos. 2005 Aug;33(8):1220-8. doi: 10.1124/dmd.104.003558. Epub 2005 May 20.
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.
乳腺癌耐药蛋白（BCRP，ABCG2）是最近发现的细胞表面转运蛋白ATP结合盒家族的成员。本研究旨在调查一系列新合成的、设计为强效P-糖蛋白抑制剂的1,4-二氢吡啶和吡啶，在体外和体内对BCRP介导的药物外排的影响。评估了25种合成的二氢吡啶和相应的吡啶以及4种市售二氢吡啶（尼莫地平、尼卡地平、硝苯地平和尼群地平）对表达BCRP的人乳腺癌MCF-7/MX100细胞和人非小细胞肺癌H460/MX20细胞中BCRP底物米托蒽醌细胞内蓄积的影响。在2.5微摩尔浓度下，25种新合成的二氢吡啶和吡啶中的24种使两种细胞系中米托蒽醌的蓄积显著增加。最有效的化合物能够使米托蒽醌的蓄积增加约4.5倍，大于用10微摩尔的夫马洁林C（一种特异性BCRP抑制剂）所获得的增加倍数。两个细胞系的结果显示出良好的相关性（r² = 0.71，p < 0.01）。尼莫地平、尼卡地平和尼群地平也表现出强效的BCRP抑制作用，而硝苯地平则无作用。二氢吡啶和吡啶化合物对米托蒽醌细胞毒性的影响与其对米托蒽醌蓄积的影响相似。将一种选定的二氢吡啶化合物I(m) [DHP-014；3-(3-(4,4-二苯基哌啶-1-基)丙基) 5-甲基 4-(3,4-二甲氧基苯基)-2,6-二甲基-1,4-二氢吡啶-3,5-二羧酸酯]与拓扑替康（一种良好的BCRP底物和中度至较差的P-糖蛋白底物）共同给药，当口服拓扑替康（2毫克/千克）与20毫克/千克 DHP-014联合使用时，导致Sprague-Dawley大鼠体内拓扑替康的全身暴露和峰浓度显著增加。观察到的拓扑替康暴露增加为这些药物在体内抑制BCRP提供了概念验证。
