Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox-active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence.

中文翻译：

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反应性脂质醛对治疗诱导的衰老的调节。

当前的理解指出，不可修复的染色体损伤是用放射或化学疗法治疗的癌细胞中加速衰老的关键决定因素。尽管如此，强效的衰老诱导剂依托泊苷不仅靶向拓扑异构酶II来诱导DNA损伤，而且还产生大量的自由基，从而增加了细胞活性氧（ROS）。为了检查DNA损伤和氧化应激在治疗诱导的衰老中的作用，我们开发了定量流式细胞仪衰老测定法，并筛选了36种氧化还原活性剂作为否则无效剂量的辐射的增强剂。尽管衰老未能与总ROS相关，但辐射增强剂，依托泊苷和其他有效的拓扑异构酶抑制剂均产生高水平的脂质过氧化作用。活性醛4-羟基-2-壬烯醛 脂质过氧化终产物足以在受辐照的细胞中诱导衰老。反过来，用肼屈嗪螯合醛可阻断依托泊苷和其他衰老诱导剂的作用。这些结果表明脂质过氧化作用增强了放射线和化学疗法对DNA的损伤，从而促进了治疗引起的衰老。