Yao Yang, Zhou Jun, Song Jing, Chen Cheng
Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People's Republic of China.
Immunopharmacol Immunotoxicol. 2025 Apr;47(2):263-271. doi: 10.1080/08923973.2025.2470344. Epub 2025 Feb 26.
Chemoresistance in gastric cancer poses a major challenge in treatment, necessitating the development of novel therapeutic strategies. This study evaluates the efficacy of ruxolitinib, a JAK1/2 inhibitor, in both sensitive and resistant gastric cancer cell lines.
Gastric cancer cell lines, including sensitive (N87 and AGS) and resistant (N87-R and AGS-R) variants, were treated with ruxolitinib alone or in combination with chemotherapeutic agents. Apoptosis induction, mitochondrial function, oxidative stress, and key signaling pathways were analyzed. Tumor growth, p-STAT3 levels, and overall survival were evaluated in xenograft models.
Ruxolitinib induced dose-dependent mitochondrial-mediated apoptosis in resistant cells and enhanced cytotoxicity in combination with chemotherapy in sensitive cells. The treatment inhibited phosphorylation of STAT3, Akt, and mTOR. Additionally, ruxolitinib reduced basal and maximal respiration rates while increasing ROS levels, suggesting mitochondrial dysfunction and oxidative stress. Resistant cells exhibited increased mitochondrial DNA content, elevated respiration rates, and higher ROS levels compared to sensitive cells, indicating alterations in mitochondrial biogenesis and redox homeostasis. These findings were supported by changes in gene expression related to mitochondrial function. In vivo, ruxolitinib significantly inhibited tumor growth and reduced p-STAT3 levels in resistant gastric cancer xenografts without causing significant weight loss. Furthermore, ruxolitinib treatment significantly prolonged overall survival in mice.
Ruxolitinib demonstrates potential in overcoming chemoresistance in gastric cancer by targeting mitochondrial function, oxidative stress, and key survival pathways. These findings support further investigation into its clinical application as an adjunct therapy for chemoresistant gastric cancer.
胃癌中的化疗耐药性给治疗带来了重大挑战，因此需要开发新的治疗策略。本研究评估了JAK1/2抑制剂鲁索替尼在敏感和耐药胃癌细胞系中的疗效。
用鲁索替尼单独或与化疗药物联合处理包括敏感（N87和AGS）和耐药（N87-R和AGS-R）变体的胃癌细胞系。分析凋亡诱导、线粒体功能、氧化应激和关键信号通路。在异种移植模型中评估肿瘤生长、p-STAT3水平和总生存期。
鲁索替尼在耐药细胞中诱导剂量依赖性的线粒体介导的凋亡，并在与化疗联合使用时增强敏感细胞的细胞毒性。该处理抑制了STAT3、Akt和mTOR的磷酸化。此外，鲁索替尼降低了基础和最大呼吸速率，同时增加了ROS水平，提示线粒体功能障碍和氧化应激。与敏感细胞相比，耐药细胞表现出线粒体DNA含量增加、呼吸速率升高和ROS水平更高，表明线粒体生物发生和氧化还原稳态发生改变。这些发现得到了与线粒体功能相关的基因表达变化的支持。在体内，鲁索替尼显著抑制耐药胃癌异种移植瘤的肿瘤生长并降低p-STAT3水平，且未导致显著体重减轻。此外，鲁索替尼治疗显著延长了小鼠的总生存期。
鲁索替尼通过靶向线粒体功能、氧化应激和关键生存途径，在克服胃癌化疗耐药性方面显示出潜力。这些发现支持进一步研究其作为化疗耐药胃癌辅助治疗的临床应用。
