Role of NF-κB and cytokine in experimental cancer cachexia

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Abstract
AIM: To assess the putative involvement of NF-κB and pro-inflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethacin (IND) on cachexia. METHODS: Thirty young male BABL/c mice were divided randomly into five groups: (a) control, (b) tumor-bearing plus saline, (c) tumor-bearing plus IND (0.25 mg•kg-1), (d) tumor-bearing plus IND (0.5 mg•kg-1), and (e) tumor-bearing plus IND (2 mg•kg-1). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 d from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNF-α and IL-6 and activity of NF-κB in the spleen were investigated in all animals. RESULTS: Weight loss was observed in all tumor-bearing mice. By day 16, body weights of non-tumor mice were about 72% of healthy controls (P < 0.01), and the weight of gastrocnemius was decreased by 28.7% (P < 0.01). No difference was found between groups in food intake (P > 0.05). Gastrocnemius weight was increased markedly (P < 0.01) after treatment of IND (0.5 mg•kg-1), while the non-tumor body weights were not significantly elevated. Tumor-bearing caused a 2-3 fold increase in serum levels of both TNF-α and IL-6 (P < 0.01). The concentration of TNF-α (P < 0.05) and IL-6 (P < 0.01) in tumor-bearing mice was reduced after administration of 0.5 mg•kg-1 IND for 7 d. But the level of IL-6 was slightly elevated following treatment of IND 2.0 mg•kg-1. NF-κB activation in the spleen was increased in tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (EMSA). NF-κB activity was reduced in mice treated with 0.5 mg•kg-1 of IND, whereas a higher NF-κB activity was observed in mice treated with 2.0 mg•kg-1 of IND. CONCLUSION: Colon 26 adenocarcinoma cells can induce severe cancer cachexia experimentally, and the mechanism may be partially due to the enhanced TNF-α and IL-6 in tumor-bearing animals, which is controlled by NF-κB. Low dose of indomethacin alleviates the cachexia, decreases the activation of NF-κB and the serum levels of TNF-α and IL-6, and prevents body weight loss and muscle atrophy, while no further effect is gained by a higher dosage.