title: Expression of the thioredoxin system in an in vivo-like cancer cell environment upon auranofin treatment.
abstract: As essential elements of the tumor microenvironment, the variable oxygenation state of the tumor tissue, the extracellular matrix (ECM) and different cell types are important determinants of carcinogenesis. These elements may also influence how tumor cells respond to therapeutic treatments. In the present study, we assessed the anti-cancer activity of auranofin and its effect on the thioredoxin (Trx) system under conditions that closely resemble the in vivo tumor microenvironment with respect to the oxygen levels and tissue architecture. We utilised an oxygen scheme involving growth of cancer cells under normoxia (20%) and hypoxia (0.1%). We also preconditioned cells with intermittent hypoxia (IH) prior to a prolonged hypoxic incubation. This oxygen scheme did not affect the cytotoxicity of auranofin; however, IH preconditioned cells were less sensitive towards the inhibition of thioredoxin reductase (TrxR) specific activity upon treatment with auranofin. IH preconditioning also upregulated Trx protein levels in auranofin treated cells. We also compared the activity of auranofin against cancer cells cultured in 2D monolayer and 3D spheroid-based culture models. Auranofin was less potent against cells grown under a more in vivo-like 3D environment. The results presented in this paper implicate the importance of the tumor oxygen environment and tissue architecture in influencing the response of cancer cells towards auranofin.
authors: School of Natural Sciences, Griffith University, Nathan, Qld 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.
authors: Maneet
authors: M
authors: Bhatia
authors: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.
authors: Carrie J
authors: CJ
authors: Lovitt
authors: School of Natural Sciences, Griffith University, Nathan, Qld 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.
authors: Prahlad V
authors: PV
authors: Raninga
authors: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.
authors: Vicky M
authors: VM
authors: Avery
authors: School of Natural Sciences, Griffith University, Nathan, Qld 4111, Australia.
authors: Giovanna
authors: G
authors: Di Trapani
authors: School of Natural Sciences, Griffith University, Nathan, Qld 4111, Australia; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia. Electronic address: K.Tonissen@griffith.edu.au.
authors: Kathryn F
authors: KF
authors: Tonissen
mesh_terms: D001310:Auranofin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D001310:Auranofin; D013879:Thioredoxins; D004317:Doxorubicin; D013880:Thioredoxin-Disulfide Reductase
keywords: 3D cell culture; Auranofin; Cancer cell microenvironment; Intermittent hypoxia; Thioredoxin