College of Pharmacy and Health Sciences, Western New England University, Springfield, Massachusetts, USA.
Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK.
FASEB J. 2023 May;37(5):e22914. doi: 10.1096/fj.202201952R.
Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.
巯基异构酶，包括 PDI、ERp57、ERp5 和 ERp72，在癌症进展、癌细胞信号转导和转移中发挥着重要而独特的作用。我们最近发现，扎鲁司特（一种 FDA 批准用于哮喘的药物）是一种泛巯基异构酶抑制剂。扎鲁司特以低微摩尔范围的 IC 抑制多种癌细胞系的生长，同时抑制细胞巯基异构酶活性、EGFR 激活和 Gab1 的下游磷酸化。扎鲁司特还通过抑制组织因子依赖性因子 Xa 的产生来阻断 OVCAR8 细胞的促凝活性。在卵巢癌异种移植模型中，在第 18 天观察到对照组与治疗组之间肿瘤大小的统计学显著差异。扎鲁司特还显著减少了模拟治疗对照组中肺部发现的转移瘤的数量和大小。当添加到化疗方案中时，与仅接受化疗治疗的小鼠相比，扎鲁司特使肿瘤生长减少了 38%，与未治疗的对照组相比减少了 83%。最后，我们在仅存在肿瘤标志物（CA-125）复发的卵巢癌女性中进行了一项试点临床试验，其中扎鲁司特治疗后 CA-125 的上升率显著降低，而未报告严重不良事件。用扎鲁司特抑制巯基异构酶代表了一种新的、耐受良好的卵巢癌治疗方法。
