Dihydroouabain, a novel radiosensitizer for cervical cancer identified by automated high-throughput screening
Dihydroouabain, a novel radiosensitizer for cervical cancer identified by automated high-throughput screening
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DOI：
10.1016/j.radonc.2020.03.047
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发表时间：
2020-07-01
影响因子：
5.7
通讯作者：
Ogawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Li, Zhihao;Tamari, Keisuke;Ogawa, Kazuhiko
背景和目的：放射治疗在宫颈癌的治疗中起着至关重要的作用，但现有的放射增敏剂在临床应用中的疗效有限。本研究的目的是建立和验证一种有效的方法，用于识别新的放射增敏剂，使用此来识别候选放射增敏剂宫颈癌，并探讨这些特定的机制时，与radiation.Materials和方法：一个自动化的平台，用于识别放射增敏剂宫颈癌的基础上创建的高通量筛选技术。从LOPAC 1280化学库的候选化合物的放射增敏作用进行了评估，在放射敏感性和放射抵抗性宫颈癌细胞使用克隆生存测定，细胞周期分析，和蛋白质印迹分析进行两个细胞line.Results：自动化高通量筛选方法确定了四个命中化合物。最有效的候选物之一是二氢哇巴因（DHO），一种Na+/K+-ATP酶抑制剂，以前未被归类为放射增敏剂。DHO显著增强宫颈癌细胞的放射敏感性。它还消除了辐射诱导的宫颈癌细胞S期阻滞。结论：DHO是一种新的宫颈癌放射增敏剂。本研究开发的自动化高通量筛选平台被证明是强大而有效的，具有广泛应用于未来放射增敏剂鉴定的潜力。(C)2020爱思唯尔B. V.保留所有权利。
Background and purpose: Radiotherapy plays a crucial role in the treatment of cervical cancer, but existing radiosensitizers have limited efficacy in clinical applications. The aims of this study were to establish and verify an efficient method for identifying new radiosensitizers, to use this to identify candidate radiosensitizers for cervical cancer, and to investigate the specific mechanisms of these when used in combination with radiotherapy.Materials and methods: An automated platform for identifying radiosensitizers for cervical cancer was created based on high-throughput screening technology. The radiosensitizing effects of candidate compounds from the LOPAC1280 chemical library were evaluated in radiosensitive and radioresistant cervical cancer cells using a clonogenic survival assay, with cell cycle analyses, and western blot analyses performed for both cell lines.Results: The automated high-throughput screening approach identified four hit compounds. One of the most potent candidates was dihydroouabain (DHO), an inhibitor of Na+/K+-ATPase that has not previously been classified as a radiosensitizer. DHO significantly enhanced radiosensitivity in cervical cancer cells. It also abrogated radiation-induced S phase arrest in cervical cancer cells. Combination treatment significantly caused the inhibition of Chk1 and increased DNA double-strand breaks (DSB).Conclusions: DHO is a novel radiosensitizer for the treatment of cervical cancer. The automated high-throughput screening platform developed in this study proved to be powerful and effective, with the potential to be widely used in the future identification of radiosensitizers. (C) 2020 Elsevier B.V. All rights reserved.