Rapid screening of antineoplastic candidates for the human organic anion transporter OATP1B3 substrates using fluorescent probes
Rapid screening of antineoplastic candidates for the human organic anion transporter OATP1B3 substrates using fluorescent probes
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DOI：
10.1016/j.canlet.2007.10.040
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发表时间：
2008-02-18
期刊：
影响因子：
9.7
通讯作者：
Mano, Nariyasu
中科院分区：
文献类型：
--
作者：
Yamaguchi, Hiroaki;Kobayashi, Minako;Mano, Nariyasu
建立了一种快速筛选系统，以提取具有有机阴离子转运多肽（OATP） 1B3有效抑制荧光底物运输的新候选物质。OATP1B3在实体消化器官癌中大量表达。因此，新的底物的鉴定导致新的策略，有效的癌症化疗与最小的不良反应。我们使用自动图像采集和分析系统（IN Cell Analyzer 1000）来可视化荧光底物chenodeoxycholyl-(N epsilon-NBD)-赖氨酸（CDCA-NBD）的运输和随后的积累。抗肿瘤筛选表明，多西紫杉醇、放线菌素D、米托蒽醌、紫杉醇和cn -38这5种候选药物对oatp1b3介导的CDCA-NBD转运具有明显的抑制作用。为了弄清这些抗肿瘤药物是否是OATP1B3的底物，我们在表达OATP1B3的细胞中进行了转运试验。我们确定SN-38是OATP1B3的新型底物。综上所述，本研究建立的筛选系统是一种从大量化合物中快速提取候选治疗药物的有效方法。2007爱思唯尔爱尔兰有限公司版权所有。
A rapid screening system has been established to extract novel candidates that exhibit potent inhibition of the transport of fluorescent substrate by organic anion transporting polypeptide (OATP) 1B3. OATP1B3 is abundantly expressed in solid digestive organ cancers. Thus, the identification of new substrates leads to novel strategies for effective cancer chemotherapy with minimal adverse effects. We used an automated image acquisition and analysis system (IN Cell Analyzer 1000) to visualize the transport and subsequent accumulation of the fluorescent substrate chenodeoxycholyl-(N epsilon-NBD)-lysine (CDCA-NBD). Antineoplastic screening demonstrated that five candidates agents, docetaxel, actinomycin D, mitoxantrone, paclitaxel, and SN-38, exhibited potent inhibitory effects on OATP1B3-mediated transport of CDCA-NBD. To clarify if these antineoplastic drugs are substrates for OATP1B3, we performed transport assays in OATP1B3-expressing cells. We determined that SN-38 is a novel substrate for OATP1B3. In conclusion, our results demonstrate that the screening system established in this study is a useful method for the rapid extraction of candidate therapeutic agents from the large numbers of compounds. (C) 2007 Elsevier Ireland Ltd. All rights reserved.