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SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation
Molecular Carcinogenesis ( IF 4.6 ) Pub Date : 2021-06-30 , DOI: 10.1002/mc.23329
Vidya Gopalakrishnan 1, 2, 3 , Shivangi Sharma 1, 2 , Ujjayinee Ray 1 , Meghana Manjunath 2, 4 , Divya Lakshmanan 1 , Supriya V Vartak 1 , Vindya K Gopinatha 1 , Mrinal Srivastava 1, 5 , Mantelingu Kempegowda 6 , Bibha Choudhary 2 , Sathees C Raghavan 1
Affiliation  

Nonhomologous end joining (NHEJ), one of the major DNA double-strand break repair pathways, plays a significant role in cancer cell proliferation and resistance to radio and chemotherapeutic agents. Previously, we had described a small molecule inhibitor, SCR7, which inhibited NHEJ in a DNA Ligase IV dependent manner. Here, we report that SCR7 potentiates the effect of γ-radiation (IR) that induces DNA breaks as intermediates to eradicate cancer cells. Dose fractionation studies revealed that coadministration of SCR7 and IR (0.5 Gy) in mice Dalton's lymphoma (DLA) model led to a significant reduction in mice tumor cell proliferation, which was equivalent to that observed for 2 Gy dose when both solid and liquid tumor models were used. Besides, co-treatment with SCR7 and 1 Gy of IR further improved the efficacy. Notably, there was no significant change in blood parameters, kidney and liver functions upon combinatorial treatment of SCR7 and IR. Further, the co-treatment of SCR7 and IR resulted in a significant increase in unrepaired DSBs within cancer cells compared to either of the agent alone. Anatomy, histology, and other studies in tumor models confirmed the cumulative effects of both agents in activating apoptotic pathways to induce cytotoxicity by modulating DNA damage response and repair pathways. Thus, we report that SCR7 has the potential to reduce the side effects of radiotherapy by lowering its effective dose ex vivo and in mice tumor models, with implications in cancer therapy.

中文翻译:

NHEJ 抑制剂 SCR7 可使肿瘤细胞对电离辐射敏感

非同源末端连接 (NHEJ) 是主要的 DNA 双链断裂修复途径之一,在癌细胞增殖和对放射和化学治疗剂的抵抗中起着重要作用。之前,我们描述了一种小分子抑制剂 SCR7,它以 DNA 连接酶 IV 依赖性方式抑制 NHEJ。在这里,我们报告说 SCR7 增强了 γ 辐射 (IR) 的作用,该辐射诱导 DNA 断裂作为根除癌细胞的中间体。剂量分级研究表明,在小鼠道尔顿淋巴瘤 (DLA) 模型中同时使用 SCR7 和 IR (0.5 Gy) 导致小鼠肿瘤细胞增殖显着减少,这与在实体和液体肿瘤模型中观察到的 2 Gy 剂量相同被使用。此外,与 SCR7 和 1 Gy 的 IR 共同处理进一步提高了疗效。尤其,SCR7和IR联合治疗后,血液参数、肾和肝功能没有显着变化。此外,与单独使用任何一种试剂相比,SCR7 和 IR 的共同治疗导致癌细胞内未修复的 DSB 显着增加。肿瘤模型的解剖学、组织学和其他研究证实了这两种药物在通过调节 DNA 损伤反应和修复途径来激活凋亡途径以诱导细胞毒性方面的累积效应。因此,我们报告说 SCR7 有可能通过降低其离体和小鼠肿瘤模型的有效剂量来减少放疗的副作用,这对癌症治疗有影响。与单独使用任何一种药物相比,SCR7 和 IR 的共同治疗导致癌细胞内未修复的 DSB 显着增加。肿瘤模型的解剖学、组织学和其他研究证实了这两种药物在通过调节 DNA 损伤反应和修复途径来激活凋亡途径以诱导细胞毒性方面的累积效应。因此,我们报告说 SCR7 有可能通过降低其离体和小鼠肿瘤模型的有效剂量来减少放疗的副作用,这对癌症治疗有影响。与单独使用任何一种药物相比,SCR7 和 IR 的共同治疗导致癌细胞内未修复的 DSB 显着增加。肿瘤模型的解剖学、组织学和其他研究证实了这两种药物在通过调节 DNA 损伤反应和修复途径来激活凋亡途径以诱导细胞毒性方面的累积效应。因此,我们报告说 SCR7 有可能通过降低其离体和小鼠肿瘤模型的有效剂量来减少放疗的副作用,这对癌症治疗有影响。
更新日期:2021-08-10
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