Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands

被引:55
作者
Allison, Simon J. [1 ]
Sadiq, Maria [2 ]
Baronou, Efstathia [3 ]
Cooper, Patricia A. [2 ]
Dunnill, Chris [1 ]
Georgopoulos, Nikolaos T. [1 ]
Latif, Ayse [4 ]
Shepherd, Samantha [1 ]
Shnyder, Steve D. [2 ]
Stratford, Ian J. [4 ]
Wheelhouse, Richard T. [3 ]
Willans, Charlotte E. [5 ]
Phillips, Roger M. [1 ]
机构
[1] Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England
[2] Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England
[3] Univ Bradford, Sch Pharm, Bradford BD7 1DP, W Yorkshire, England
[4] Univ Manchester, Div Pharm & Optometry, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England
[5] Univ Leeds, Sch Chem, Woodhouse Lane, Leeds LS2 9JT, W Yorkshire, England
关键词
Silver-N-heterocyclic carbene; Thioredoxin reductase inhibitor; Topoisomerase inhibitor; PARP1; inhibitor; Glycolytic inhibitor; THIOREDOXIN REDUCTASE; DNA-BINDING; MAMMALIAN THIOREDOXIN; TUMOR-GROWTH; CANCER; INHIBITORS; CYTOTOXICITY; APOPTOSIS; TARGET; AGENTS;
D O I
10.1016/j.canlet.2017.04.041
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. Crown Copyright (C) 2017 Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:98 / 107
页数:10
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