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吡唑并[3,4-d]嘧啶衍生物 SCO-201 逆转 ABCG2/BCRP 介导的多药耐药。

The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP.

机构信息

Department of Drug Design and Pharmacology, University of Copenhagen, 1165 Copenhagen, Denmark.

Pharmaceutical Institute, University of Bonn, 53113 Bonn, Germany.

出版信息

Cells. 2020 Mar 4;9(3):613. doi: 10.3390/cells9030613.

DOI:10.3390/cells9030613
PMID:32143347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7140522/
Abstract

ATP-binding cassette (ABC) transporters, such as breast cancer resistance protein (BCRP), are key players in resistance to multiple anti-cancer drugs, leading to cancer treatment failure and cancer-related death. Currently, there are no clinically approved drugs for reversal of cancer drug resistance caused by ABC transporters. This study investigated if a novel drug candidate, SCO-201, could inhibit BCRP and reverse BCRP-mediated drug resistance. We applied in vitro cell viability assays in SN-38 (7-Ethyl-10-hydroxycamptothecin)-resistant colon cancer cells and in non-cancer cells with ectopic expression of BCRP. SCO-201 reversed resistance to SN-38 (active metabolite of irinotecan) in both model systems. Dye efflux assays, bidirectional transport assays, and ATPase assays demonstrated that SCO-201 inhibits BCRP. In silico interaction analyses supported the ATPase assay data and suggest that SCO-201 competes with SN-38 for the BCRP drug-binding site. To analyze for inhibition of other transporters or cytochrome P450 (CYP) enzymes, we performed enzyme and transporter assays by in vitro drug metabolism and pharmacokinetics studies, which demonstrated that SCO-201 selectively inhibited BCRP and neither inhibited nor induced CYPs. We conclude that SCO-201 is a specific, potent, and potentially non-toxic drug candidate for the reversal of BCRP-mediated resistance in cancer cells.

摘要

三磷酸腺苷结合盒（ABC）转运蛋白，如乳腺癌耐药蛋白（BCRP），是多种抗癌药物耐药的关键因素，导致癌症治疗失败和癌症相关死亡。目前，尚无临床批准的药物可逆转 ABC 转运蛋白引起的癌症药物耐药性。本研究探讨了一种新型药物候选物 SCO-201 是否可以抑制 BCRP 并逆转 BCRP 介导的药物耐药性。我们应用体外细胞活力测定法在 SN-38（伊立替康的活性代谢物）耐药结肠癌细胞和异位表达 BCRP 的非癌细胞中进行了研究。SCO-201 在这两种模型系统中均逆转了对 SN-38（伊立替康的活性代谢物）的耐药性。染料外排测定、双向转运测定和 ATP 酶测定表明 SCO-201 抑制 BCRP。计算机相互作用分析支持 ATP 酶测定数据，并表明 SCO-201 与 SN-38 竞争 BCRP 的药物结合位点。为了分析对其他转运蛋白或细胞色素 P450（CYP）酶的抑制作用，我们通过体外药物代谢和药代动力学研究进行了酶和转运蛋白测定，结果表明 SCO-201 选择性抑制 BCRP，既不抑制也不诱导 CYP。我们得出结论，SCO-201 是一种特异性、强效且潜在无毒的药物候选物，可用于逆转癌细胞中 BCRP 介导的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/be88110d5955/cells-09-00613-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/4ab78371ac19/cells-09-00613-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/1995b00131a3/cells-09-00613-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/54e9a359bd8b/cells-09-00613-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/78ba9c709ef8/cells-09-00613-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/cdec3a6af737/cells-09-00613-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/27da08f973ad/cells-09-00613-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/be88110d5955/cells-09-00613-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/4ab78371ac19/cells-09-00613-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/1995b00131a3/cells-09-00613-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/54e9a359bd8b/cells-09-00613-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/78ba9c709ef8/cells-09-00613-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/cdec3a6af737/cells-09-00613-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/27da08f973ad/cells-09-00613-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9361/7140522/be88110d5955/cells-09-00613-g007.jpg

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