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.

中文翻译：

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硫氧还蛋白系统在金诺芬治疗后在体内样癌细胞环境中的表达。

作为肿瘤微环境的基本要素，肿瘤组织的可变氧合作用状态，细胞外基质（ECM）和不同细胞类型是致癌作用的重要决定因素。这些元素也可能影响肿瘤细胞对治疗的反应。在本研究中，我们在氧水平和组织结构方面非常类似于体内肿瘤微环境的条件下，评估了金诺芬的抗癌活性及其对硫氧还蛋白（Trx）系统的影响。我们利用了一种氧气方案，该方案涉及在常氧（20％）和低氧（0.1％）下的癌细胞的生长。在长时间缺氧孵育之前，我们还对细胞进行了间歇性缺氧（IH）预处理。这种氧气方案不影响金诺芬的细胞毒性。然而，用金诺芬处理后，IH预处理的细胞对抑制硫氧还蛋白还原酶（TrxR）比活性的敏感性较低。IH预处理还可以在金诺芬处理过的细胞中上调Trx蛋白水平。我们还比较了金诺芬对在2D单层和3D椭球基培养模型中培养的癌细胞的活性。金诺芬对在更像体内的3D环境下生长的细胞的效力较弱。本文提出的结果暗示了肿瘤氧环境和组织结构在影响癌细胞对金诺芬的反应中的重要性。我们还比较了金诺芬对在2D单层和3D椭球基培养模型中培养的癌细胞的活性。金诺芬对在更像体内的3D环境下生长的细胞的效力较弱。本文提出的结果暗示了肿瘤氧环境和组织结构在影响癌细胞对金诺芬的反应中的重要性。我们还比较了金诺芬对在2D单层和3D椭球基培养模型中培养的癌细胞的活性。金诺芬对在更像体内的3D环境下生长的细胞的效力较弱。本文提出的结果暗示了肿瘤氧环境和组织结构在影响癌细胞对金诺芬的反应中的重要性。