Chemotherapeutic drugs induce oxidative stress associated with DNA repair and metabolism modulation.
Chemotherapeutic drugs induce oxidative stress associated with DNA repair and metabolism modulation.
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DOI：
10.1016/j.lfs.2021.120242
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发表时间：
2021-12
期刊：
影响因子：
6.1
通讯作者：
Yujie Zhang;Chunyang Ding;Wenkang Zhu;Xinyu Li;Techang Chen;Qingxi Liu;Sa Zhou;Tong-Cun Zhang-Tong-Cu
中科院分区：
文献类型：
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作者：
Yujie Zhang;Chunyang Ding;Wenkang Zhu;Xinyu Li;Techang Chen;Qingxi Liu;Sa Zhou;Tong-Cun Zhang-Tong-Cu
诱导大体积DNA损伤的化疗癌症药物如顺铂（CIS）和阿霉素（DOX）通常用于治疗多种癌症。然而，它们经常引起多器官毒性，其机制尚不清楚。利用细胞模型，本研究表明，持续内源性活性氧（ROS）刺激后，单剂量短期处理CIS和DOX。ROS水平与DNA双链断裂（DSB）的形成相关。敲低BRCA 1，参与同源重组（HR）的关键球员，增强ROS的积累。而敲低DNA-PKcs并过表达BRCA 1以抑制非同源末端连接（NHEJ）修复途径并恢复HR可以部分抑制活性氧水平。这些数据表明ROS的产生与DSB的形成和修复相关，DSB的形成和修复可能是DNA修复的下游事件。进一步的研究表明，敲低的DNA修复调节因子PP 2A（而非ATM）也可以部分减少ROS。ROS的诱导影响促炎细胞因子白细胞介素1β（IL-1β）、白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α）的水平。总的来说，目前的研究表明，DNA修复相关的代谢变化和氧化应激可能是与遗传毒性化疗药物相关的严重副作用的直接原因。
Bulky DNA damage inducing chemotherapeutic cancer drugs such as cisplatin (CIS) and doxorubicin (DOX) are commonly used in the treatment of a variety of cancers. However, they often cause multi-organ toxicity, and the mechanisms underlying are not clear. Using cellular model, the present study showed that persistent endogenous reactive oxygen species (ROS) were stimulated after a single dose short treatment with CIS and DOX. ROS level correlated with the formation of DNA double-strand breaks (DSBs). Knockdown BRCA1, a key player involved in homologous recombination (HR), enhanced ROS accumulation. Whereas knockdown DNA-PKcs and overexpress BRCA1 to inhibit nonhomologous end-joining (NHEJ) repair pathway and restore HR can partially suppress ROS levels. These data indicated that ROS production is associated with DSB formation and repair which is likely a downstream event of DNA repair. Further studies showed that knockdown DNA repair regulators PP2A but not ATM, could partially reduce ROS too. The induction of ROS affected the level of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Collectively, the present study reveals that DNA repair associated metabolism change and oxidative stress may be a direct cause of the severe side effects associated with genotoxic chemotherapy cancer drugs.