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

Simon J. Allison, Maria Sadiq, Efstathia Baronou, Patricia A. Cooper, Chris Dunnill, Nikolaos T. Georgopoulos, Ayşe Latif, Samantha Shepherd, Steve D. Shnyder, Ian J. Stratford, Richard T. Wheelhouse, Charlotte E. Willans, Roger M. Phillips

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Abstract

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 I/II 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.
LanguageEnglish
Pages98-107
Number of pages10
JournalCancer Letters
Volume403
Early online date15 Jun 2017
Publication statusPublished - 10 Sep 2017

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Silver
Ligands
Neoplasms
dicarbine
temozolomide
DNA Damage
Thioredoxin-Disulfide Reductase
DNA Repair Enzymes
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Glycolysis
Cisplatin
carbene
Reactive Oxygen Species
Cell Death
Apoptosis

Cite this

Allison, Simon J. ; Sadiq, Maria ; Baronou, Efstathia ; Cooper, Patricia A. ; Dunnill, Chris ; Georgopoulos, Nikolaos T. ; Latif, Ayşe ; Shepherd, Samantha ; Shnyder, Steve D. ; Stratford, Ian J. ; Wheelhouse, Richard T. ; Willans, Charlotte E. ; Phillips, Roger M. / Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands. In: Cancer Letters. 2017 ; Vol. 403. pp. 98-107.
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abstract = "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 I/II 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.",
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Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands. / Allison, Simon J.; Sadiq, Maria; Baronou, Efstathia; Cooper, Patricia A.; Dunnill, Chris; Georgopoulos, Nikolaos T.; Latif, Ayşe; Shepherd, Samantha; Shnyder, Steve D.; Stratford, Ian J.; Wheelhouse, Richard T.; Willans, Charlotte E.; Phillips, Roger M.

In: Cancer Letters, Vol. 403, 10.09.2017, p. 98-107.

Research output: Contribution to journalArticle

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AU - Phillips, Roger M.

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