Fazzari Francesco, Chow Sue, Cheung May, Barghout Samir H, Schimmer Aaron D, Chang Qing, Hedley David
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
ACS Pharmacol Transl Sci. 2022 Oct 12;5(11):1070-1078. doi: 10.1021/acsptsci.2c00170. eCollection 2022 Nov 11.
Pancreatic ductal adenocarcinoma is characterized by increased generation of reactive oxygen species that can cause lethal oxidative stress. Here, we evaluated the combined inhibition of the glutathione and thioredoxin antioxidant systems in preclinical models of pancreatic ductal adenocarcinoma, using buthionine sulfoximine (BSO) that targets glutathione synthesis, and auranofin that targets thioredoxin recycling. BSO potentiated the cytotoxicity of auranofin and induced lethal oxidative stress in primary pancreatic cancer cells. As assessed by the cellular thermal shift assay, auranofin engaged with thioredoxin reductase 1 in primary cells at concentrations known to induce cell death. Moreover, we used imaging mass cytometry to map the biodistribution of atomic gold in patient-derived xenografts treated with auranofin, and the drug was readily detectable throughout the epithelial and stromal compartments after treatment with a clinically relevant dose. In conclusion, combinatorial treatment with BSO and auranofin could serve as a potential therapeutic strategy in pancreatic ductal adenocarcinoma.
胰腺导管腺癌的特征是活性氧生成增加，这会导致致命的氧化应激。在此，我们在胰腺导管腺癌的临床前模型中评估了谷胱甘肽和硫氧还蛋白抗氧化系统的联合抑制作用，使用了靶向谷胱甘肽合成的丁硫氨酸亚砜胺（BSO）和靶向硫氧还蛋白循环利用的金诺芬。BSO增强了金诺芬的细胞毒性，并在原发性胰腺癌细胞中诱导了致命的氧化应激。通过细胞热位移分析评估，金诺芬在已知诱导细胞死亡的浓度下与原代细胞中的硫氧还蛋白还原酶1结合。此外，我们使用成像质谱流式细胞术来绘制用金诺芬治疗的患者来源异种移植瘤中原子金的生物分布，在用临床相关剂量治疗后，该药物在整个上皮和基质区室中都易于检测到。总之，BSO和金诺芬联合治疗可作为胰腺导管腺癌的一种潜在治疗策略。
