FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models
FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models
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DOI：
10.1016/j.bcp.2017.11.009
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发表时间：
2018-01-01
影响因子：
5.8
通讯作者：
Perego, Paola
中科院分区：
文献类型：
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作者：
Corno, Cristina;Stucchi, Simone;Perego, Paola
XPO 1/CRM 1抑制剂selinexor（KPT-330）目前正在多项临床试验中作为抗癌药物进行评估。XPO 1参与FoxO-1的核输出，我们以前发现在铂耐药卵巢癌中FoxO-1减少。本研究的目的是确定使用selinexor富集FoxO-1核定位是否会增加卵巢癌细胞对顺铂的敏感性。Selinexor单药对不同的卵巢癌细胞株均有明显的抗增殖作用。在顺铂敏感的IGF-I中发现了赛林克斯与顺铂组合的时间表依赖性协同效应，组合功效在敏感细胞中比在耐药细胞中更明显。在IGF-I细胞中，当顺铂暴露后使用赛灵克斯时，该组合更有效。蛋白质印迹法发现参与凋亡的蛋白质（p53，Bax）和参与细胞周期进程的蛋白质（p21（WAF 1））的调节。硒处理的细胞表现出丰富的FoxO-1核染色。RNA干扰的敲除实验表明，FOXO 1沉默的细胞显示出对selinexor的敏感性降低。FOXO 1沉默也倾向于降低选定顺铂浓度下药物组合的疗效。Selinexor显著抑制肿瘤生长，诱导FoxO-1核定位，并提高顺铂在IGF-I异种移植物中的功效。总之，我们的结果支持FoxO-1作为促进对selinexor敏感性的关键因素之一，以及顺铂和selinexor在具有选定分子背景的卵巢癌细胞中的协同相互作用，突出了针对分子肿瘤特征定制治疗方案的必要性。(C)2017爱思唯尔公司All rights reserved.
The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines. A schedule-dependent synergistic effect of selinexor in combination with cisplatin was found in cisplatin-sensitive IGROV-1, the combination efficacy being more evident in sensitive than in the resistant cells. In IGROV-1 cells, the combination was more effective when selinexor followed cisplatin exposure. A modulation of proteins involved in apoptosis (p53, Bax) and in cell cycle progression (p21(WAF1))) was found by Western blotting. Selinexor-treated cells exhibited enriched FoxO-1 nuclear staining. Knock-down experiments with RNA interference indicated that FOXO1-silenced cells displayed a reduced sensitivity to selinexor. FOXO1 silencing also tended to reduce the efficacy of the drug combination at selected cisplatin concentrations. Selinexor significantly inhibited tumor growth, induced FoxO-1 nuclear localization and improved the efficacy of cisplatin in IGROV-1 xenografts. Taken together, our results support FoxO-1 as one of the key factors promoting sensitivity towards selinexor and the synergistic interaction between cisplatin and selinexor in ovarian carcinoma cells with selected molecular backgrounds, highlighting the need for treatment regimens tailored to the molecular tumor features. (C) 2017 Elsevier Inc. All rights reserved.