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Identification and characterization of novel SCR7-based small-molecule inhibitor of DNA end-joining, SCR130 and its relevance in cancer therapeutics.
Molecular Carcinogenesis ( IF 3.0 ) Pub Date : 2020-03-18 , DOI: 10.1002/mc.23186
Ujjayinee Ray 1 , Sanjay Kumar Raul 1 , Vindya K Gopinatha 2 , Dipayan Ghosh 1 , Kanchugarakoppal S Rangappa 2 , Kempegowda Mantelingu 2 , Sathees C Raghavan 1
Affiliation  

Targeting DNA repair with small-molecule inhibitors is an attractive strategy for cancer therapy. Majority of DNA double-strand breaks in mammalian cells are repaired through nonhomologous end-joining (NHEJ). It has been shown that small-molecule inhibitors of NHEJ can block efficient repair inside cancer cells, leading to cell death. Previously, we have reported that SCR7, an inhibitor of NHEJ can induce tumor regression in mice. Later studies have shown that different forms of SCR7 can inhibit DNA end-joining in Ligase IV-dependent manner. Recently, we have derivatized SCR7 by introducing spiro ring into core structure. Here, we report the identification of a novel inhibitor of NHEJ, named SCR130 with 20-fold higher efficacy in inducing cytotoxicity in cancer cell lines. SCR130 inhibited DNA end-joining catalyzed by rat tissue extract. Specificity analysis revealed that while SCR130 was specific to Ligase IV, it showed minimal or no effect on Ligase III and Ligase I mediated joining. Importantly, SCR130 exhibited the least cytotoxicity in Ligase IV-null cell line as compared with wild type, confirming Ligase IV-specificity. Furthermore, we demonstrate that SCR130 can potentiate the effect of radiation in cancer cells when used in combination with γ-radiation. Various cellular assays in conjunction with Western blot analysis revealed that treatment with SCR130 led to loss of mitochondrial membrane potential leading to cell death by activating both intrinsic and extrinsic pathways of apoptosis. Thus, we describe a novel inhibitor of NHEJ with higher efficacy and may have the potential to be developed as cancer therapeutic.

中文翻译:

DNA末端连接的新型基于SCR7的小分子抑制剂SCR130的鉴定和表征及其在癌症治疗中的相关性。

用小分子抑制剂靶向DNA修复是癌症治疗的一种有吸引力的策略。哺乳动物细胞中的大多数DNA双链断裂通过非同源末端连接(NHEJ)修复。已经显示,NHEJ的小分子抑制剂可以阻断癌细胞内部的有效修复,从而导致细胞死亡。以前,我们已经报道了NHEJ的抑制剂SCR7可以诱导小鼠肿瘤消退。后来的研究表明,不同形式的SCR7可以以Ligase IV依赖的方式抑制DNA末端连接。最近,我们通过将螺环引入芯结构来衍生化SCR7。在这里,我们报告鉴定了一种新型NHEJ抑制剂SCR130,在诱导癌细胞系中的细胞毒性方面具有20倍的更高功效。SCR130抑制了大鼠组织提取物催化的DNA末端连接。特异性分析表明,虽然SCR130对Ligase IV具有特异性,但对Ligase III和Ligase I介导的连接作用很小或没有影响。重要的是,与野生型相比,SCR130在Ligase IV无细胞系中表现出最小的细胞毒性,从而证实Ligase IV特异性。此外,我们证明SCR130与γ射线结合使用时,可以增强癌细胞中的辐射效果。各种细胞分析与Western印迹分析相结合,揭示了通过激活细胞凋亡的内在和外在途径,用SCR130处理导致线粒体膜电位丧失,从而导致细胞死亡。因此,我们描述了一种具有更高功效的新型NHEJ抑制剂,可能具有开发为癌症治疗剂的潜力。
更新日期:2020-03-18
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