Modulation of therapy-induced senescence by reactive lipid aldehydes
Modulation of therapy-induced senescence by reactive lipid aldehydes
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DOI：
10.1038/cddiscovery.2016.45
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发表时间：
2016-01-01
影响因子：
7
通讯作者：
Kron, S. J.
中科院分区：
文献类型：
--
作者：
Flor, A. C.;Doshi, A. P.;Kron, S. J.
目前的认识指出，不可修复的染色体损伤是放射或化疗治疗的癌细胞加速衰老的关键决定因素。尽管如此，强大的衰老诱导剂依托泊苷不仅针对拓扑异构酶II诱导DNA损伤，而且还产生大量的自由基，增加细胞内的活性氧自由基(ROS)。为了研究DNA损伤和氧化应激在治疗诱导衰老中的作用，我们开发了一种流式细胞仪衰老定量分析方法，并筛选出36种氧化还原活性物质作为原本无效的辐射剂量的增强剂。虽然衰老与总ROS没有相关性，但辐射增强剂、依托泊苷和其他有效的拓扑异构酶抑制剂都产生了高水平的脂质过氧化。反应性醛4-羟基-2-壬烯醛是一种脂质过氧化的最终产物，足以诱导辐照细胞衰老。反过来，用肼来隔离醛可以阻止依托泊苷和其他衰老诱导剂的作用。这些结果表明，脂质过氧化加剧了放射和化疗导致的DNA损伤，从而推动了治疗诱导的衰老。
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.