Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux

被引：43
作者：
Bormio Nunes, Julia H. [1 ,2 ]
Hager, Sonja [3 ,4 ]
Mathuber, Marlene [1 ]
Posa, Vivien [5 ,6 ]
Roller, Alexander [1 ]
Enyedy, Eva A. [5 ,6 ]
Stefanelli, Alessia [3 ]
Berger, Walter [3 ,4 ]
Keppler, Bernhard K. [1 ,4 ]
Heffeter, Petra [3 ,4 ]
Kowol, Christian R. [1 ,4 ]
机构：
[1] Univ Vienna, Fac Chem, Inst Inorgan Chem, A-1090 Vienna, Austria
[2] Univ Campinas UNICAMP, Inst Chem, Inorgan Chem Dept, BR-13083970 Campinas, SP, Brazil
[3] Med Univ Vienna, Inst Canc Res, A-1090 Vienna, Austria
[4] Res Cluster Translat Canc Therapy Res, A-1090 Vienna, Austria
[5] Univ Szeged, Interdisciplinary Excellence Ctr, Dept Inorgan & Analyt Chem, H-6720 Szeged, Hungary
[6] Univ Szeged, MTA SZTE Lendulet Funct Met Complexes Res Grp, H-6720 Szeged, Hungary
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 22期
基金：
奥地利科学基金会;
关键词：
D O I：
10.1021/acs.jmedchem.0c01277
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones. Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure-activity relationships. SW480/Coti cells were found to overexpress ABCC1, and COTI-2 being a substrate for this efflux pump. This was unexpected, as ABCC1 has strong selectivity for glutathione adducts. The recognition by ABCC1 could be explained by the reduction kinetics of a ternary Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones.
引用
收藏
页码：13719 / 13732
页数：14
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