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Trisulfide linked cholesteryl PEG conjugate attenuates intracellular ROS and collagen-1 production in a breast cancer co-culture model
Biomaterials Science ( IF 6.6 ) Pub Date : 2020-11-24 , DOI: 10.1039/d0bm01544j
Nam V. Dao 1, 2, 3, 4, 5 , Francesca Ercole 1, 2, 3, 4, 5 , Matthew C. Urquhart 1, 2, 3, 4, 5 , Lisa M. Kaminskas 6, 7, 8, 9 , Cameron J. Nowell 4, 5, 9, 10, 11 , Thomas P. Davis 1, 2, 3, 4, 5 , Erica K. Sloan 4, 5, 9, 10, 11 , Michael R. Whittaker 1, 2, 3, 4, 5 , John F. Quinn 1, 2, 3, 4, 5
Affiliation  

The progression of cancer has been closely-linked with augmentation of cellular reactive oxygen species (ROS) levels and ROS-associated changes in the tumour microenvironment (TME), including alterations to the extracellular matrix and associated low drug uptake. Herein we report the application of a co-culture model to simulate the ROS based cell–cell interactions in the TME using fibroblasts and breast cancer cells, and describe how novel reactive polymers can be used to modulate those interactions. Under the co-culture conditions, both cell types exhibited modifications in behaviour, including significant overproduction of ROS in the cancer cells, and elevation of the collagen-1 secretion and stained actin filament intensity in the fibroblasts. To examine the potential of using reactive antioxidant polymers to intercept ROS communication and thereby manipulate the TME, we employed H2S-releasing macromolecular conjugates which have been previously demonstrated to mitigate ROS production in HEK cells. The specific conjugate used, mPEG-SSS-cholesteryl (T), significantly reduced ROS levels in co-cultured cancer cells by approximately 50%. This reduction was significantly greater than that observed with the other positive antioxidant controls. Exposure to T was also found to downregulate levels of collagen-1 in the co-cultured fibroblasts, while exhibiting less impact on cells in mono-culture. This would suggest a possible downstream effect of ROS-mitigation by T on stromal-tumour cell signalling. Since fibroblast-derived collagens modulate crucial steps in tumorigenesis, this ROS-associated effect could potentially be harnessed to slow cancer progression. The model may also be beneficial for interrogating the impact of antioxidants on naturally enhanced ROS levels, rather than relying on the application of exogenous oxidants to simulate elevated ROS levels.

中文翻译:

在乳腺癌共培养模型中,三硫键连接的胆固醇基PEG共轭物可减弱细胞内ROS和1型胶原的产生

癌症的进展与细胞活性氧(ROS)水平的增加以及肿瘤微环境(TME)中ROS相关的变化密切相关,包括细胞外基质的改变和相关的低药物吸收。在这里,我们报道了共培养模型在使用成纤维细胞和乳腺癌细胞模拟TME中基于ROS的细胞间相互作用的应用,并描述了如何使用新型反应性聚合物来调节这些相互作用。在共培养条件下,两种细胞类型均表现出行为上的改变,包括癌细胞中ROS的显着过量产生,以及成纤维细胞中1型胶原蛋白分泌和肌动蛋白丝染色强度的升高。先前已证明可减轻HEK细胞中ROS生成的2 S释放大分子缀合物。所用的特异性缀合物mPEG-SSS-胆固醇( T)可将共培养癌细胞中的ROS水平显着降低约50%。这种降低明显大于其他抗氧化剂阳性对照所观察到的降低。还发现暴露于T会下调共培养的成纤维细胞中1型胶原的水平,而在单培养中对细胞的影响较小。这表明T可能减轻ROS的下游影响。在基质肿瘤细胞信号转导上。由于成纤维细胞胶原蛋白调节肿瘤发生过程中的关键步骤,因此这种与ROS相关的作用可能会被利用来减缓癌症的进展。该模型对于询问抗氧化剂对天然增强的ROS水平的影响也可能是有益的,而不是依赖于外源氧化剂的应用来模拟升高的ROS水平。
更新日期:2020-12-16
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