Wang Chao, Zha Yin-Lin, Wang Hao, Sun Bai, Qiang Wei-Guang, Yuan Ye, Shi Hong-Bing, Hu Wen-Wei
Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China.
Department of Radiation Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, PR China.
Transl Oncol. 2025 Jul;57:102393. doi: 10.1016/j.tranon.2025.102393. Epub 2025 May 1.
Iodine-125 (I) seed brachytherapy has been applied to treat various malignant tumors such as esophageal cancer, however, radioresistance can reduce its efficacy. Endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) is one of the core mechanisms of I seed radiation-induced cell death, thus aggravating ERS has been considered a promising sensitization strategy. Herein, we show that combination therapy of an irreversible proteasome inhibitor carfilzomib (CFZ) and I seed radiation displayed strong anti-tumor effect on esophageal squamous cell carcinoma (ESCC). Mechanistically, ERS and UPR regulated multiple cell death modalities induced by the combination therapy, including apoptosis, paraptosis, and ferroptosis. I seed radiation induced reactive oxygen species (ROS) production, DNA damage, p53 activation, and apoptosis. CFZ promoted ROS production, and augmented I seed radiation-induced apoptosis via the mitochondrial pathway, which was mediated by the UPR-C/EBP homologous protein (CHOP) pathway and was independent of the p53 pathway. CFZ enhanced I seed radiation-induced intracellular Ca overload, protein ubiquitination, ERS, and UPR, consequently promoting paraptosis. I seed radiation induced accumulation of intracellular Fe and lipid peroxides but upregulated the expression of ferroptosis inhibitors, SLC7A11 and glutathione peroxidase 4 (GPX4). The combination therapy promoted ferroptosis by enhancing the accumulation of intracellular Fe and downregulating GPX4 expression. The mouse experiment demonstrated that CFZ can promote the efficacy of I seed radiation with good tolerance. Our findings suggest that combination therapy of I seed radiation and CFZ is associated with multiple cell death modalities and may serve as a promising therapeutic strategy for ESCC.
碘-125（I）粒子近距离放射治疗已被应用于治疗各种恶性肿瘤，如食管癌，然而，放射抗性会降低其疗效。内质网应激（ERS）及随后的未折叠蛋白反应（UPR）是I粒子辐射诱导细胞死亡的核心机制之一，因此加重ERS被认为是一种有前景的增敏策略。在此，我们表明不可逆蛋白酶体抑制剂卡非佐米（CFZ）与I粒子辐射的联合治疗对食管鳞状细胞癌（ESCC）显示出强大的抗肿瘤作用。机制上，ERS和UPR调节联合治疗诱导的多种细胞死亡方式，包括凋亡、副凋亡和铁死亡。I粒子辐射诱导活性氧（ROS）产生、DNA损伤、p53激活和凋亡。CFZ促进ROS产生，并通过线粒体途径增强I粒子辐射诱导的凋亡，这由UPR-C/EBP同源蛋白（CHOP）途径介导且独立于p53途径。CFZ增强I粒子辐射诱导的细胞内钙超载、蛋白质泛素化、ERS和UPR，从而促进副凋亡。I粒子辐射诱导细胞内铁和脂质过氧化物积累，但上调铁死亡抑制剂溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达。联合治疗通过增强细胞内铁的积累和下调GPX4表达促进铁死亡。小鼠实验表明CFZ可提高I粒子辐射的疗效且耐受性良好。我们的研究结果表明，I粒子辐射与CFZ的联合治疗与多种细胞死亡方式相关，可能是ESCC一种有前景的治疗策略。
