Zhu Yingwei, Chu Yunqian, Dai Hanjue, Lu Enci, Geng Qian, Xian Qingying, Jiang Hua, Zhu Wenyu
Department of Oncology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213100, China.
Pulmonary Department, The Third People's Hospital of Changzhou, Changzhou, 213100, China.
Pulm Pharmacol Ther. 2025 Sep;90:102362. doi: 10.1016/j.pupt.2025.102362. Epub 2025 Jun 3.
Kushenol, a monomeric compound, was extracted from the roots of the medicinal plant Sophora flavescens. To explore the activity of Kushenol A in non-small cell lung cancer (NSCLC), CCK-8 assay, flow cytometry, and Western blot were performed. A xenograft mouse model was established. Our results demonstrated that Kushenol A treatment significantly enhanced the killing effect of radiation on NSCLC cells. Co-treatment with radiation and Kushenol A markedly reduced cell viability, increased intracellular ROS levels, and elevated the proportion of apoptotic cells compared to NSCLC cells treated with radiation alone. Animal experiments further confirmed that radiation therapy with simultaneous Kushenol A administration suppressed tumor growth and improved radiotherapy sensitivity compared to mice treated with radiation alone. Furthermore, Kushenol A did not produce significant toxic damage to the major organs of mice. Mechanistically, radiation therapy combined with Kushenol A treatment significantly upregulated protein levels of cleaved Caspase-3 and cleaved Caspase-9, leading to Bax translocation from the cytoplasm to mitochondria. Concurrently, Kushenol A treatment reduced NRF2 levels in the cytoplasm, thereby promoting an increase in ROS levels. Notably, Kushenol A enhanced tumor radiosensitivity by targeted inhibition of Indoleamine 2,3-dioxygenase 1 (IDO1). Taken together, our findings suggested that cotreatment with Kushenol A and radiation promoted the entry of Bax into mitochondria and activated the mitochondrial apoptotic pathway. Kushenol A exhibited targeted inhibition of IDO1, enhancing the sensitivity of non-small cell lung cancer to radiotherapy.
苦参醇是一种单体化合物，从药用植物苦参的根部提取。为了探究苦参醇A在非小细胞肺癌（NSCLC）中的活性，进行了CCK-8检测、流式细胞术和蛋白质免疫印迹分析。建立了异种移植小鼠模型。我们的结果表明，苦参醇A处理显著增强了辐射对NSCLC细胞的杀伤作用。与单独接受辐射治疗的NSCLC细胞相比，辐射与苦参醇A联合处理显著降低了细胞活力，增加了细胞内活性氧（ROS）水平，并提高了凋亡细胞的比例。动物实验进一步证实，与单独接受辐射治疗的小鼠相比，同时给予苦参醇A的放射治疗抑制了肿瘤生长并提高了放射治疗敏感性。此外，苦参醇A对小鼠的主要器官未产生明显的毒性损伤。机制上，放射治疗联合苦参醇A处理显著上调了裂解的半胱天冬酶-3和裂解的半胱天冬酶-9的蛋白水平，导致 Bax 从细胞质转移到线粒体。同时，苦参醇A处理降低了细胞质中NRF2的水平，从而促进了ROS水平的升高。值得注意的是，苦参醇A通过靶向抑制吲哚胺2,3-双加氧酶1（IDO1）增强了肿瘤放射敏感性。综上所述，我们的研究结果表明，苦参醇A与辐射联合治疗促进了Bax进入线粒体并激活了线粒体凋亡途径。苦参醇A对IDO1具有靶向抑制作用，增强了非小细胞肺癌对放射治疗的敏感性。
