Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Drug Metab Dispos. 2013 Jul;41(7):1404-13. doi: 10.1124/dmd.112.050021. Epub 2013 Apr 25.
AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1- and SLCO1B3-transfected cell systems compared with the mock-transfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.
AR-67（7-t-丁基二甲基硅基-10-羟基喜树碱）是一种亲脂性喜树碱类似物，目前处于临床前研究阶段。由于其在肿瘤组织中的表达，转运蛋白已知会对喜树碱的处置和一般化疗药物的反应产生影响。因此，我们研究了乳腺癌耐药蛋白（BCRP）、多药耐药蛋白 1（MDR1）和有机阴离子转运多肽（OATP）1B1/1B3 转运蛋白与 AR-67 之间的相互作用及其对 AR-67 毒性特征的影响。使用表达上述转运蛋白的细胞系，我们表明亲脂性 AR-67 内酯形式是外排转运蛋白 BCRP 和 MDR1 的底物。此外，与 mock 转染相比，OATP1B1 和 OATP1B3 促进了 AR-67 羧酸在 SLCO1B1 和 SLCO1B3 转染细胞系统中的摄取。值得注意的是，BCRP 和 MDR1 均赋予 AR-67 内酯耐药性。鉴于最近的研究表明某些癌症类型中 OATP1B3 表达增加，我们研究了 OATP1B3 表达对暴露于 AR-67 羧酸后细胞活力的影响。与 mock 转染细胞相比，OATP1B3 表达细胞的羧酸摄取量增加，但未被敏化，因为内酯的细胞内量是羧酸的 50 倍，并且在 OATP1B3 表达和 OATP1B3 非表达细胞之间相当。总之，AR-67 内酯的 BCRP 和 MDR1 介导的外排赋予了 AR-67 耐药性，但 OATP1B3 介导的 AR-67 羧酸摄取不会使 OATP1B3 表达的肿瘤细胞敏感。
