Singh Kuljeet, Tarapcsák Szabolcs, Gyöngy Zsuzsanna, Ritter Zsuzsanna, Batta Gyula, Bosire Rosevalentine, Remenyik Judit, Goda Katalin
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary.
Pharmaceutics. 2021 Dec 2;13(12):2062. doi: 10.3390/pharmaceutics13122062.
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug-drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.
P-糖蛋白（Pgp，ABCB1）是被称为ABC转运蛋白的最大活性转运蛋白家族之一的成员。由于其在具有屏障功能的组织中的表达及其广泛的底物谱，它是许多药物吸收、代谢和排泄的重要决定因素。Pgp和/或其他一些药物转运ABC蛋白（如ABCG2、MRP1）在几乎所有癌症和癌症干细胞中过度表达，癌细胞由此对许多药物产生耐药性。因此，抑制Pgp可能是对抗耐药癌细胞的一种策略。先前的研究表明，某些多酚与人类Pgp相互作用。我们测试了15种酸樱桃来源的多酚对Pgp的基础和维拉帕米刺激的ATP酶活性、钙黄绿素-AM和柔红霉素转运的影响，以及使用构象敏感的UIC2单克隆抗体对Pgp构象的影响。我们发现槲皮素、槲皮素-3-葡萄糖苷、水仙苷和鞣花酸抑制了Pgp的ATP酶活性，并增加了Pgp阳性细胞中钙黄绿素和柔红霉素的积累。矢车菊素-3-O-槐糖苷、儿茶素、柚皮素、花青素和咖啡酸增加了Pgp的ATP酶活性，而它们对荧光Pgp底物的细胞内积累影响较弱。包括表儿茶素、反式阿魏酸、oenin、锦葵色素和绿原酸在内的几种测试多酚在所有应用的测定中均无效。有趣的是，儿茶素和表儿茶素虽然是立体异构体，但表现不同。我们还研究了槲皮素、柚皮素和鞣花酸与维拉帕米联合添加对Pgp转运活性的影响。在这些实验中，我们发现测试多酚和维拉帕米的转运抑制作用是相加的或协同的。一般来说，我们的数据表明测试多酚与Pgp存在多种相互作用。我们的结果还提醒人们注意与饮食多酚与涉及Pgp底物/抑制剂药物的化疗同时使用相关的药物-药物相互作用（DDIs）的潜在风险。
