Exposure to arsenic (As) mainly through contaminated drinking water enhances the lung tumor progression, invasion, and metastasis. The carcinogenic effect of As is due to the generation of reactive oxygen species (ROS) and DNA damage, and interference with DNA repair machinery. Herein, we investigated the potential therapeutic function of quercetin on As-treated lung cancer cells. Quercetin is a natural product with antioxidative, anti-inflammatory, and antiproliferative properties. We showed that quercetin induced cell death in the As-exposed lung cancer cells in a dose-dependent manner. Quercetin was able to significantly inhibit the proliferation of the As-treated cells over a period of 5 weeks. In addition, quercetin induced ROS-mediated DNA double-strand breaks in the As-treated lung cancer cells. We also showed that ROS generation induced by quercetin activated caspase-3 to a sufficient level to induce DNA damage but insufficient to induce death in As-treated lung cancer cells. Moreover, transient activation of caspase-2 was detected in quercetin- and As-cotreated cells. The flow cytometry-based cell cycle analysis showed that the antiproliferative function of quercetin was mediated by S-phase cell cycle arrest, which was associated with upregulation of the Ataxia Telangiectasia-mutated (ATM), but not ATM and RAD3-related. In conclusion, quercetin synergized the As-driven ROS generation and DNA damage, and induced the S-phase arrest, thus inhibiting the proliferation of As-exposed lung cancer cells. This data suggested that quercetin is an alternative reagent to chemo-drugs to prevent the growth of As-exposed lung cancer cells.

中文翻译：

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槲皮素通过半胱天冬酶依赖性 DNA 损伤信号减弱砷相关肺癌细胞的增殖

主要通过受污染的饮用水接触砷 (As) 会增强肺肿瘤的进展、侵袭和转移。As 的致癌作用是由于产生活性氧 (ROS) 和 DNA 损伤，以及干扰 DNA 修复机制。在此，我们研究了槲皮素对 As 处理的肺癌细胞的潜在治疗功能。槲皮素是一种具有抗氧化、抗炎和抗增殖特性的天然产物。我们发现槲皮素以剂量依赖性方式诱导暴露于 As 的肺癌细胞中的细胞死亡。槲皮素能够在 5 周内显着抑制经 As 处理的细胞的增殖。此外，槲皮素在 As 处理的肺癌细胞中诱导 ROS 介导的 DNA 双链断裂。我们还表明，槲皮素诱导的 ROS 生成激活 caspase-3 到足以诱导 DNA 损伤但不足以诱导 As 处理的肺癌细胞死亡的水平。此外，在槲皮素和 As 共处理的细胞中检测到 caspase-2 的瞬时激活。基于流式细胞术的细胞周期分析表明，槲皮素的抗增殖功能是由 S 期细胞周期阻滞介导的，这与 Ataxia Telangiectasia-mutated (ATM) 的上调有关，但与 ATM 和 RAD3 无关。总之，槲皮素协同 As 驱动的 ROS 生成和 DNA 损伤，并诱导 S 期阻滞，从而抑制 As 暴露的肺癌细胞的增殖。该数据表明，槲皮素是化学药物的替代试剂，可防止暴露于 As 的肺癌细胞生长。