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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.
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Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Sadiq, Maria
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Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Baronou, Efstathia
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Univ Bradford, Sch Pharm, Bradford BD7 1DP, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Cooper, Patricia A.
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Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Dunnill, Chris
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Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Georgopoulos, Nikolaos T.
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Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

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Shepherd, Samantha
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Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Shnyder, Steve D.
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Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Stratford, Ian J.
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Univ Manchester, Div Pharm & Optometry, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Wheelhouse, Richard T.
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Univ Bradford, Sch Pharm, Bradford BD7 1DP, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Willans, Charlotte E.
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机构:
Univ Leeds, Sch Chem, Woodhouse Lane, Leeds LS2 9JT, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England

Phillips, Roger M.
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Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England Univ Huddersfield, Sch Appl Sci, Huddersfield HD1 3DH, W Yorkshire, England
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
来源:
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.
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页码:98 / 107
页数:10
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Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China

Fung, Yi-Man Eva
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Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China

Chow, Pui-Keong
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Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China

Wan, Pui-Ki
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Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China

Che, Chi-Ming
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Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
Univ Hong Kong, Dept Chem, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
HKU Shenzhen Inst Res & Innovat, Shenzhen 518053, Peoples R China Univ Hong Kong, State Key Lab Synthet Chem, Inst Mol Funct Mat, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China
[10]
The structure of human thioredoxin reductase 1 provides insights into C-terminal rearrangements during catalysis
[J].
Fritz-Wolf, Karin
;
Urig, Sabine
;
Becker, Katja
.
JOURNAL OF MOLECULAR BIOLOGY,
2007, 370 (01)
:116-127

Fritz-Wolf, Karin
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机构: Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany

Urig, Sabine
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机构: Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany

Becker, Katja
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h-index: 0
机构:
Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany Univ Giessen, Interdisciplinary Res Ctr, D-35392 Giessen, Germany