Ruxolitinib enhances gastric cancer to chemotherapy by suppressing JAK/STAT3 and inducing mitochondrial dysfunction and oxidative stress.

Abstract

Objective: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.