印度巴巴原子研究中心Santosh K. Sandur团队发现，Nrf-2抑制剂丙酸氯倍他索通过线粒体ROS依赖性铁死亡使人类肺癌细胞对辐射诱导的杀伤敏感。相关论文于2024年3月13日在线发表在《中国药理学报》杂志上。

研究人员评估了合成糖皮质激素丙酸氯倍他索（CP）在A549人肺癌细胞中的放射增敏疗效。CP通过抑制Nrf-2通路，导致氧化应激升高，从而对肺癌细胞表现出强效的放射增敏作用。转录组研究显示，与铁死亡、脂肪酸和谷胱甘肽代谢有关的通路受到了明显的调节。

与这些研究结果一致的是，CP处理后的辐射照射显示出线粒体肿胀、破裂和嵴缺失等铁死亡的特征。铁死亡是由铁依赖性ROS积累和脂质过氧化引发的一种调节性细胞死亡。在与辐射结合使用时，CP显示出铁释放、线粒体ROS和脂质过氧化的增强，表明铁死亡的诱导。

此外，铁螯合、抑制脂质过氧化或清除线粒体ROS都能阻止CP介导的放射致敏作用。Nrf-2通过上调抗氧化防御和铁平衡负向调节铁死亡。有趣的是，Nrf-2过表达的A549细胞对CP介导的铁死亡诱导和放射致敏具有耐受性。因此，这项研究发现，抗银屑病药物丙酸氯倍他索可作为一种有前途的放射增敏剂，用于治疗Keap-1突变型肺癌。

据悉，放疗与Nrf-2抑制剂相结合有望成为治疗放射耐药肺癌的一种潜在策略。

附：英文原文

Title: Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis

Author: Rai, Archita, Patwardhan, Raghavendra S., Jayakumar, Sundarraj, Pachpatil, Pradnya, Das, Dhruv, Panigrahi, Girish Ch., Gota, Vikram, Patwardhan, Sejal, Sandur, Santosh K.

Issue&Volume: 2024-03-13

Abstract: Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.

DOI: 10.1038/s41401-024-01233-8

Source: https://www.nature.com/articles/s41401-024-01233-8