Role of NF-κB and cytokine in experimental cancer cachexia

AIM:To assess the putative involvement of NF-κB and pro-inflammatory cytokines in the pathogenesis of cancercachexia and the therapeutic efficacy of indomethacin (IND)on cachexia.METHODS:Thirty young male BABL/c mice were dividedrandomly into five groups:(a) control,(b) tumor-bearingplus saline,(c) tumor-bearing plus IND (0.25 mg·kg-1),(d)tumor-bearing plus IND (0.5 mg·kg-1),and (e) tumor-bearingplus IND (2 mg·kg-1).Colon 26 adenocarcinoma cells ofmurine were inoculated subcutaneously to induce cachexia.Saline and IND were given intraperitoneally daily for 7 daysfrom the onset of cachexia to sacrifice.Food intake andbody composition were documented,serum levels of TNF-α and IL-6 and activity of NF-κB in the spleen wereinvestigated in all animals.RESULTS:Weight loss was observed in all tumor-bearingmice.By day 16,body weights of non-tumor mice wereabout 72% of healthy controls (P<0.01),and the weight ofgastrocnemius was decreased by 28.7% (P<0.01).Nodifference 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-tumorbody weights were not significantly elevated.Tumor-bearingcaused a 2-3 fold increase in serum levels of both TNF-αand 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 afteradministration of 0.5 mg·kg-1IND for 7 days.But the levelof IL-6 was slightly elevated following treatment of IND 2.0mg·kg-1.NF-κB activation in the spleen was increased intumor-bearing mice in comparison with controls inelectrophoretic mobility shift assay (EMSA).NF-κB activitywas reduced in mice treated with 0.5 mg·kg-1of IND,whereasa higher NF-κB activity was observed in mice treated with2.0 mg·kg-1of IND.CONCLUSION:Colon 26 adenocarcinoma cells can inducesevere cancer cachexia experimentally,and themechanism may be partially due to the enhanced TNF-αand IL-6 in tumor-bearing animals,which is controlled byNF-κB.Low dose of indomethacin alleviates the cachexia,decreases the activation of NF-κB and the serum levelsof TNF-α and IL-6,and prevents body weight loss andmuscle atrophy,while no further effect is gained by ahigher dosage.