Amelioration of cancer cachexia with preemptive administration of tumor necrosis factor-α blocker.

Cancer cachexia is syndrome accompanying weight reduction, fat loss, muscle atrophy in patients with advanced cancer. Since tumor necrosis factor-α (TNF-α) played pivotal role in cancer cachexia, we hypothesized preemptive administration of TNF-α antibody might mitigate cancer cachexia. Detailed molecular mechanisms targeting muscle atrophy, cachexic inflammation, and catabolic catastrophe were explored whether TNF-α antibody can antagonize these cachexic mechanisms. Stimulated with preliminary finding human antibody, infliximab or adalimumab, significantly inhibited TNF-α as well as their signals relevant to cachexia in mice, preemptive administration of 1.5 mg/kg adalimumab was done in C-26-induced cancer cachexia. Adalimumab significantly mitigated cancer cachexia manifested with significantly lesser weight loss, leg muscle preservation, and higher survival compared to cachexia control ( p <0.05). Significant ameliorating action of muscle atrophy were accompanied significant decreases of muscle-specific UPS like atrogin-1/MuRF-1, Pax-7, PCG-1α, and Mfn-2 after adalimumab ( p <0.01) and significantly attenuated lipolysis with inhibition of ATGL HSL, and MMPs. Cachexic factors including IL-6 expression, serum IL-6, gp130, IL-6R, JAK2, and STAT3 were significantly inhibited with adalimumab ( p <0.01). Genes implicated in cachexic inflammation like NF-κB, c- Jun /c- Fos , and MAPKs were significantly repressed, while mTOR/AKT was significantly increased adalimumab ( p <0.05). Conclusively, preemptive administration of adalimumab can be tried in high risk to cancer cachexia.
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