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

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ALLISON, Simon J., SADIQ, Maria, BARONOU, Efstathia, COOPER, Patricia A., DUNNILL, Chris, GEORGOPOULOS, Nik, LATIF, Ayşe, SHEPHERD, Samantha, SHNYDER, Steve D., STRATFORD, Ian J., WHEELHOUSE, Richard T., WILLANS, Charlotte E. and PHILLIPS, Roger M. (2017). Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands. Cancer letters, 403, 98-107. [Article]

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33182:640666

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33182:640666

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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.

More Information

Official URL:

https://www.sciencedirect.com/science/article/pii/...

Uncontrolled Keywords:

Cell Line, Tumor; Humans; Neoplasms; DNA Damage; Cisplatin; Reactive Oxygen Species; Organometallic Compounds; Dacarbazine; Imidazoles; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA-Binding Proteins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antigens, Neoplasm; Inhibitory Concentration 50; Signal Transduction; Apoptosis; Cell Survival; Glycolysis; Oxidative Stress; Dose-Response Relationship, Drug; Drug Synergism; Drug Resistance, Neoplasm; Thioredoxin Reductase 1; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Poly (ADP-Ribose) Polymerase-1; Temozolomide; Glycolytic inhibitor; PARP1 inhibitor; Silver-N-heterocyclic carbene; Thioredoxin reductase inhibitor; Topoisomerase inhibitor; Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Cisplatin; DNA Damage; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA-Binding Proteins; Dacarbazine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Glycolysis; Humans; Imidazoles; Inhibitory Concentration 50; Neoplasms; Organometallic Compounds; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Reactive Oxygen Species; Signal Transduction; Temozolomide; Thioredoxin Reductase 1; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; 1112 Oncology and Carcinogenesis; Oncology & Carcinogenesis; 3211 Oncology and carcinogenesis

Page Range:

98-107

Event Location:

Ireland

Identifiers

Identification Number:

10.1016/j.canlet.2017.04.041

ORCID for Nik Georgopoulos: