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

Description

Yes / 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. / RMP and MS funded by Yorkshire Cancer Research (pump priming grant BPP 046). IJS and AL funded by NIHR Research & Innovation Division, Strategic Project Funding 2013 and Manchester Pharmacy School Fellowship.

Links & Downloads

1. Allison SJ, Sadiq M, Baronou E et al (2017) Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbine ligands. Cancer Letters. 403: 98-107.
2. http://hdl.handle.net/10454/11960
3. https://doi.org/10.1016/j.canlet.2017.04.041

Tags

Silver-N-heterocyclic carbene

Thioredoxin reductase inhibitor

Topoisomerase inhibitor

PARP1 inhibitor

Glycolytic inhibitor

Additional Fields

Identifer	oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/11960
Date	15 June 2017
Creators	Allison, Simon J., Sadiq, Maria, Baronou, Efstathia, Cooper, Patricia A., Dunnill, C., Georgopoulos, N.T., Latif, A., Shepherd, S.L., Shnyder, Steven, Stratford, I.J., Wheelhouse, Richard T., Willans, C., Phillips, Roger M.
Source Sets	Bradford Scholars
Language	English
Detected Language	English
Type	Article, Accepted Manuscript
Rights	© 2017 Elsevier. Reproduced in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.