Westhoff Gina L, Chen Yi, Teng Nelson N H
*Division of Gynecologic Oncology, Legacy Health, Portland, OR; and †Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA.
Int J Gynecol Cancer. 2017 Jun;27(5):887-894. doi: 10.1097/IGC.0000000000000969.
Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo.
Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets.
Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo.
Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
在84%的卵巢癌病例中存在异常激活的叉头框蛋白M1（FOXM1），其导致细胞增殖失控和FOXM1转录网络失调。已证实，噻唑类抗生素硫链丝菌素可降低FOXM1表达。我们旨在确定用硫链丝菌素靶向FOXM1通路是否能在体外提高紫杉醇和顺铂对人卵巢癌腹水细胞的疗效。
用紫杉醇、顺铂、硫链丝菌素或其组合处理人卵巢癌细胞系和患者腹水细胞48小时，并评估细胞毒性。采用Chou和Talalay方法计算组合指数值来确定药物联合效应。进行定量实时聚合酶链反应以确定FOXM1表达及其下游靶点的变化。
卵巢癌细胞系和患者腹水癌细胞中FOXM1表达水平均过表达。用硫链丝菌素靶向FOXM1可降低FOXM1 mRNA表达及其下游靶点如细胞周期蛋白B1（CCNB1）、细胞周期蛋白依赖性激酶25B（CDC25B）的表达，导致细胞系和患者腹水癌细胞死亡。此外，在体外，将硫链丝菌素添加到紫杉醇和顺铂中对化疗耐药的卵巢癌患者腹水细胞显示出协同作用。
靶向FOXM1可能为化疗耐药的上皮性卵巢癌带来新的治疗方法。
