Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc- inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

中文翻译：

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辐射诱导的脂质过氧化触发铁死亡并与铁死亡诱导剂协同作用。

尽管辐射被广泛用于治疗癌症，但耐药机制通常会发展并涉及 DNA 修复的激活和细胞凋亡的抑制。因此，通过替代细胞死亡途径使癌细胞对辐射敏感的化合物是有价值的。我们在此报告铁死亡（一种由脂质过氧化驱动的非凋亡性细胞死亡形式）是辐射诱导的癌细胞死亡的部分原因。此外，我们发现通过系统 xc 抑制或 GPX4 抑制激活铁死亡的小分子与辐射协同作用，通过增强细胞质脂质过氧化而不增加 DNA 损伤或半胱天冬酶活化来诱导几种癌症类型的铁死亡。铁死亡诱导剂与细胞质辐照协同作用，但与核辐照无协同作用。最后，在小鼠异种移植模型和人类患者衍生的肺腺癌和神经胶质瘤模型中，铁死亡诱导剂的施用增强了辐射的抗肿瘤作用。这些结果表明，铁死亡诱导剂可能是有效的放射增敏剂，可以扩大放射治疗的疗效和适应症范围。