Role of NF-kappaB and cytokine in experimental cancer cachexia

Abstract

Aim: To assess the putative involvement of NF-kappaB 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 x kg(-1)), (d) tumor-bearing plus IND (0.5 mg x kg(-1)), and (e) tumor-bearing plus IND (2 mg x kg(-1)). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNF-alpha and IL-6 and activity of NF-kappaB 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 x 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-alpha and IL-6 (P<0.01). The concentration of TNF-alpha (P<0.05) and IL-6 (P<0.01) in tumor-bearing mice was reduced after administration of 0.5 mg x kg(-1) IND for 7 days. But the level of IL-6 was slightly elevated following treatment of IND 2.0 mg x kg(-1). NF-kappaB activation in the spleen was increased in tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (EMSA). NF-kappaB activity was reduced in mice treated with 0.5 mg x kg(-1) of IND, whereas a higher NF-kappaB activity was observed in mice treated with 2.0 mg x 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-alpha and IL-6 in tumor-bearing animals, which is controlled by NF-kappaB. Low dose of indomethacin alleviates the cachexia, decreases the activation of NF-kappaB and the serum levels of TNF-alpha and IL-6, and prevents body weight loss and muscle atrophy, while no further effect is gained by a higher dosage.

Figure 1

Activation of NF-κB in spleen. Lane a represents the control group, Lane b, c, d, e represents the group of tumor-bearing plus saline, indomethacin 0.25 mg•kg^-1, 0.5 mg•kg^-1, 2 mg•kg^-1, respectively.