摘要
背景:恶性胸膜间皮瘤(MPM)是一种石棉相关肿瘤,预后差,治疗方案少。JQ 1是BRD 4的选择性拮抗剂,对癌基因的转录有调节作用。其他,包括MPM耐药相关的c-Myc和Fra-1。 目的:探讨JQ1是否能提高顺铂抗MPM的疗效。 方法:检测顺铂联合JQ 1对代表肿瘤细胞表型的MPM细胞株(上皮样细胞、肉瘤样细胞和bipas细胞)的抗增殖活性。在一条顺铂耐药亚线上。采用三维球体模型对组合方案进行了优化。药物联合作用与细胞周期分布和衰老有关-联合β-半乳糖苷酶阳性细胞。免疫印迹法和RT-qPCR法检测c-Myc和Fra-1蛋白的表达及部分凋亡标记物的表达.DNA损伤和修复的评估NS碱性彗星试验。 结果:JQ1联合顺铂可诱导MPM细胞增殖,或协同(超加性)抗增殖作用。该组合显示肿瘤消退。在三维球体模型上。它诱导细胞凋亡增加,c-Myc降低,有时甚至Fra-1表达降低.JQ 1可减少顺铂诱导的MPM细胞DNA断裂,增加细胞衰老。NCE即使在不太熟练的细胞中也是如此,从而增强了DNA损伤反应(DDR)。 结论:c-Myc抑制是超相加效应的结果.随后的DDR增强触发凋亡诱导和/或永久生长停止(衰老),取决于MPM细胞。AR上下文,导致肿瘤消退。因此,BET活性的药物调节可能是未来MPM治疗的一个很有前途的工具。
关键词: 恶性间皮瘤,BET溴域抑制,JQ 1,表观遗传学,铂基化疗,c-Myc,Fra-1。
图形摘要
Current Cancer Drug Targets
Title:JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells
Volume: 18 Issue: 8
关键词: 恶性间皮瘤,BET溴域抑制,JQ 1,表观遗传学,铂基化疗,c-Myc,Fra-1。
摘要: Background: Malignant Pleural Mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance-associated c-Myc and Fra-1.
Objective: We investigated if JQ1 could enhance the efficacy of cisplatin against MPM.
Methods: The antiproliferative activity of cisplatin in combination with JQ1 was assessed on MPM cell lines representative of the cellular phenotypes of this tumor (epithelioid, sarcomatoid and biphasic), and on one cisplatin resistant sub-line. The combination schedule was optimized adopting a 3Dspheroid model. Drug combination effects were correlated with cell cycle distribution and senescence- associated β-galactosidase positive cells. The expression of c-Myc and Fra-1 proteins and some apoptosis markers was assessed by immunoblotting and RT-qPCR. DNA damage and repair were evaluated by means of alkaline comet assay.
Results: JQ1 in combination with cisplatin elicited additive or synergistic (superadditive) antiproliferative effects on MPM cells, depending on the cell line. The combination showed tumor regression on the 3D-spheroid model. It induced increased apoptosis, along with decreased c-Myc and, sometimes, Fra-1 expression. JQ1 decreased cisplatin-induced DNA breaks in all MPM cells and increased senescence even in less proficient cells, thus enhancing the DNA Damage Response (DDR).
Conclusion: The superadditive effect is due to c-Myc repression. The consequent DDR enhancement triggers to apoptosis induction and/or permanent growth arrest (senescence), depending on the MPM cellular context, leading to tumor regression. Thus, the pharmacological modulation of BET activity could represent a promising tool for future MPM therapy.
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JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells, Current Cancer Drug Targets 2018; 18 (8) . https://dx.doi.org/10.2174/1568009617666170623101722
DOI https://dx.doi.org/10.2174/1568009617666170623101722 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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