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.
| 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., CC-BY-NC-ND |
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