Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure-activity relationship
Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure-activity relationship
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DOI：
10.1007/s00280-007-0426-7
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发表时间：
2007-11-01
影响因子：
3
通讯作者：
Sugimoto, Yoshikazu
中科院分区：
文献类型：
--
作者：
Katayama, Kazuhiro;Masuyama, Kazuto;Sugimoto, Yoshikazu
目的：三磷酸腺苷结合盒(ABC)转运蛋白如P-糖蛋白(P-gp)、乳腺癌耐药蛋白(BCRP)和多药耐药相关蛋白1(MRP1)等与多种抗癌药物耐药有关。我们以前曾报道过一些黄酮类化合物具有BCRP抑制活性。方法采用细胞生长抑制法检测了不同类黄酮类化合物对BCRP、P-gp和MRP1介导的人白血病K562细胞和转染人表皮样癌KB-3-1细胞的逆转作用。从生长抑制曲线确定IC50值。然后将RI50值确定为使每个转染体的IC50降低两倍的抑制物浓度。结果筛选出32个化合物具有BCRP抑制活性，其中20个化合物具有活性。其中3‘，4’，7-三甲氧基黄酮的抗BCRP活性最强，对SN-38的RI50值为0.012 mU M，对米托蒽酮的RI50值为0.044 mU M。接下来，我们研究了11种化合物对P-gp和MRP1介导的耐药性的影响。其中3‘，4’，7-三甲氧基黄酮和金合欢素仅有较低的抗P-gp活性，其余的对P-gp无抑制作用。结论我们的研究结果表明，许多黄酮类化合物仅选择性地抑制BCRP。此外，我们从我们目前的研究中检验了结构与BCRP抑制活性的关系。
Purpose ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-related protein 1 (MRP1), confer resistance to various anticancer agents. We previously reported that some flavonoids have BCRP-inhibitory activity. Here we show the reversal effects of an extensive panel of flavonoids upon BCRP-, P-gp-, and MRP1-mediated drug resistance.Methods Reversal effects of flavonoids upon BCRP-, P-gp-, or MRP1-mediated drug resistance were examined in the BCRP- or MDR1-transduced human leukemia K562 cells or in the MRP1-transfected human epidermoid carcinoma KB-3-1 cells using cell growth inhibition assays. The IC50 values were determined from the growth inhibition curves. The RI50 values were then determined as the concentration of inhibitor that causes a twofold reduction of the IC50 in each transfectant. The reversal of BCRP activity was tested by measuring the fluorescence of intracellular topotecan.Results The BCRP-inhibitory activity of 32 compounds was screened, and 20 were found to be active. Among these active compounds, 3',4',7-trimethoxyflavone showed the strongest anti-BCRP activity with RI50 values of 0.012 mu M for SN-38 and 0.044 mu M for mitoxantrone. We next examined the effects of a panel of 11 compounds on P-gp- and MRP1-mediated drug resistance. Two of the flavones, 3',4',7-trimethoxyflavone and acacetin, showed only low anti-P-gp activity, with the remainder displaying no suppressive effects against P-gp. None of the flavonoids that we tested inhibited MRP1.Conclusion Our present results thus indicate that many flavonoids selectively inhibit BCRP only. Moreover, we examined the structure-BCRP inhibitory activity relationship from our current study.