在高级别卵巢癌细胞中,溴域抑制剂i-BET858触发了一种独特的转录反应,与增强的DNA损伤、细胞周期阻滞和细胞凋亡相关。

IF 5.7 2区 医学 Q1 Medicine
Marcos Quintela, David W James, Agne Pociute, Lydia Powell, Kadie Edwards, Zoe Coombes, Jetzabel Garcia, Neil Garton, Nagindra Das, Kerryn Lutchman-Singh, Lavinia Margarit, Amy L Beynon, Inmaculada Rioja, Rab K Prinjha, Nicola R Harker, Deyarina Gonzalez, R Steven Conlan, Lewis W Francis
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引用次数: 1

摘要

背景:卵巢癌具有特殊的未满足的临床需求,在晚期疾病的妇女中观察到持续较低的5年生存率,需要继续努力开发新的治疗方案。BRD4在高级别浆液性卵巢癌(HGSC)的显著亚群中的扩增导致了BET抑制剂(BETi)作为有前途的抗肿瘤药物的发展,这些药物随后在I/II期临床试验中进行了评估。在这里,我们描述了i-BET858的分子效应和体外临床前活性,i-BET858是一种被证明具有体内BRD抑制活性的二价泛bet抑制剂。结果:i-BET858在HGSC临床样本的细胞系和原代细胞中均表现出比前代BETis更强的细胞毒活性。在分子水平上,i-BET858触发了两部分转录反应,包括一个通常与实体肿瘤中BET抑制相关的基因“核心”网络,以及一个独特的i-BET858基因标记。与i-BET151相比,i-BET858在机制上引起了DNA损伤、细胞周期阻滞和细胞凋亡。结论:总的来说,我们的离体和体外研究表明,i-BET858是进一步临床验证治疗HGSC的最佳候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells.

Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells.

Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells.

Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells.

Background: Ovarian cancer has a specific unmet clinical need, with a persistently poor 5-year survival rate observed in women with advanced stage disease warranting continued efforts to develop new treatment options. The amplification of BRD4 in a significant subset of high-grade serous ovarian carcinomas (HGSC) has led to the development of BET inhibitors (BETi) as promising antitumour agents that have subsequently been evaluated in phase I/II clinical trials. Here, we describe the molecular effects and ex vivo preclinical activities of i-BET858, a bivalent pan-BET inhibitor with proven in vivo BRD inhibitory activity.

Results: i-BET858 demonstrates enhanced cytotoxic activity compared with earlier generation BETis both in cell lines and primary cells derived from clinical samples of HGSC. At molecular level, i-BET858 triggered a bipartite transcriptional response, comprised of a 'core' network of genes commonly associated with BET inhibition in solid tumours, together with a unique i-BET858 gene signature. Mechanistically, i-BET858 elicited enhanced DNA damage, cell cycle arrest and apoptotic cell death compared to its predecessor i-BET151.

Conclusions: Overall, our ex vivo and in vitro studies indicate that i-BET858 represents an optimal candidate to pursue further clinical validation for the treatment of HGSC.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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