Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany.
Eur J Med Chem. 2015 Mar 6;92:723-31. doi: 10.1016/j.ejmech.2015.01.011. Epub 2015 Jan 8.
Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.
抗肿瘤化合物用于治疗多种癌症。抗肿瘤化合物发挥其活性的有效性在很大程度上取决于参与化合物进入细胞的转运蛋白，以及将其推出细胞的转运蛋白。有机阴离子转运多肽 1B1（OATP1B1）和有机阴离子转运多肽 1B3（OATP1B3）属于 SLCO 蛋白家族，特异性表达于肝脏的窦状膜，已知与多种药物相互作用。本研究涉及这些蛋白与癌症化疗中常用的抗肿瘤化合物的相互作用。使用 [(3)H]标记的雌酮 3-硫酸盐和 [(3)H]标记的胆囊收缩素八肽（CCK-8）作为底物，在稳定转染的人胚肾细胞中对蛋白质 OATP1B1 和 OATP1B3 进行了功能表征。在存在抗肿瘤化合物的情况下进行的底物摄取实验表明，长春碱和紫杉醇与 OATP1B1 强烈相互作用，Ki 值分别为 10.2 μM 和 0.84 μM。OATP1B3 与多种抗肿瘤化合物（包括苯丁酸氮芥、米托蒽醌、长春碱、长春新碱、紫杉醇和依托泊苷）表现出高度显著的相互作用，Ki 值分别为 40.6 μM、3.2 μM、15.9 μM、30.6 μM、1.8 μM 和 13.5 μM。我们报告了转运蛋白 OATP1B1 和 OATP1B3 的几种新的相互作用，强调了需要研究它们在药物相互作用和癌症化疗中的作用。
