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

Abstract

Cancer cachexia is syndrome accompanying weight reduction, fat loss, muscle atrophy in patients with advanced cancer. Since tumor necrosis factor-alpha (TNF-alpha) played pivotal role in cancer cachexia, we hypothesized preemptive administration of TNF-alpha antibody might mitigate cancer cachexia. Detailed molecular mechanisms targeting muscle atrophy, cachexic inflammation, and catabolic catastrophe were explored whether TNF-alpha antibody can antagonize these cachexic mechanisms. Stimulated with preliminary finding human antibody, infliximab or adalimumab, significantly inhibited TNF-alpha 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-1 alpha, 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-kappa B, 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.