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

IF 2.9 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2025-04-01 Epub Date: 2025-02-26 DOI:10.1080/08923973.2025.2470344

Yang Yao, Jun Zhou, Jing Song, Cheng Chen

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引用次数: 0

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.

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).