Combined Use Of Rosiglitazone With Imidapril Alleviates Cancer Cachexia In A Mouse Model

Objective: Rosiglitazone (RGZ) and imidapril improve cancer cachexia via differentmechanisms. We aimed to compare these two drugs, alone or in combination, incancer cachexia in mice.Methords: Forty male BALB/C mice aged6-8weeks were randomly divided intohealthy control, placebo, RGZ, imidapril, and RGZ+imidapril groups. Latter4groupswere injected with colon-26adenocarcinoma and treated9days later with RGZ andimidapril alone or in combination for7days. Body weight, tumor volume, wet weightof gastrocnemius muscle and epididymal adipose, serum levels of nutritional markersand cytokines, expression of nuclear factor-κB (NF-κB) and ATP-dependentubiquitin-proteasome proteolysis-promoting genes atrogin-1and MuRF-1weremeasured.RESULTS：Generally condition：Tumors were palpable in mice initially on day5or6afterinoculation of tumor cells.Day9was chosen for establishment of cachexia since byDay9, the non-tumor weighs of the tumor-bearing mice are significantly differentfrom those of healthy mice, together with apparent cachexic signs and symptoms(poor physical, asthenia, piloerection, shedding, and non-glossy fur), compared withthe control group was significantly different (p<0.05),which entered the state ofcachexia.Food intake：There was no difference in food intake among the groups (P>0.05).Tumor volume：The tumors of tumor-bearing mice could be touched from Day5on.The increase in tumor volume of mice treated with RGZ, imidapril alone orRGZ+imidapril was slower than that of mice treated with placebo. On Day16, micetreated with RGZ, imidapril, and RGZ+imidapril had a significantly smaller tumorvolume (final tumor volume) than mice treated with placebo.Body weight: The body weight of mice in the five groups had no significantdifferences between them at the beginning and for several days. There was nodifference in body weight among the groups at the end of the experiment (P>0.05).Tumor weight and tumor-free body weight: On Day9, the non-tumor weights ofthe tumor-bearing mice were significantly different from healthy control mice,together with apparent cachexic signs and symptoms. On Day16, the tumor weightsof groups RGZ, imidapril and RGZ+imidapril were significantly lower than that ofthe placebo group, and a significantly lower tumor-free body weight was found in alltreatment groups compared to that of the healthy control group. Treatment with RGZ,imidapril and RGZ+imidapril showed tumor-free body weight change by7.5%,8.8%,9.8%respectively (all, p<0.05as compared to placebo group).Muscle weight and adipose weight: RGZ, imidapril, and RGZ+imidapril treatmentinduced a tendency to wet weight of gastrocnemius muscle and epididymal adiposegain were significantly higher than placebo group (all, P<0.05), however, as compared to healthy control group they were significantly lower (all, P<0.01).Metabolic indicator: All tumor-bearing mice had a significantly lower level of serumtotal protein (STP), serum albumin (Alb) and blood glucose (Glu) campared withhealthy control animals (all, p<0.01). The concentrations of serum total protein (STP),serum albumin (Alb) and blood glucose (Glu) level showed significant differencebetween placebo group and RGZ+imidapril-treated group [(48.60±3.67) g/L vs(53.63±2.57) g/L, P<0.01;(14.61±1.40) g/L vs (15.94±0.68) g/L, P<0.05;(1.50±0.61)mmol/L vs (3.33±1.10) mmol/L, P<0.01; respectively]. Treatment with imidaprilshowed a level of blood glucose (Glu) change by63.3%(P<0.05as compared toplacebo group). Treatment with imidapril could decrease level of serum triglyceride(Tg) as compared to placebo and healthy control groups (all, P<0.01). Placebo andRGZ+imidapril-treated groups were significantly higher than healthy control group inserum triglyceride (Tg)(P<0.05). Treatment with RGZ had an94.7%increase inserum triglyceride (Tg) compared to healthy control group, however this was notstatistically significant due to the high variability.Serum factors: For the serum level of TNF-a and IL-6, All tumor-bearing mice weresignificantly higher than healthy control mice (all, P<0.01). Serum level of TNF-awas significantly lower in RGZ, imidapril and RGZ+imidapril-treated than in placeboanimials (all, P<0.01). RGZ, imidapril and RGZ+imidapril treatment induced atendency to serum level of IL-6desrease by12.7%,19.8%,33.5%respectively butwas not different from placebo group (all, P>0.05). All treatment groups were lowerlevel expression of serum insulin than healthy control group, however, only placebogroup was significantly lower as compared to healthy control group [(199.20±33.83)ng/L vs (332.72±41.08) ng/L, P<0.05]. Treatment with RGZ showed a significantchange by51.5%about the level expression of serum insulin (p<0.05as compared toplacebo group).The expression of NF-κB: Treatment with RGZ and RGZ+imidapril group couldsignificant restrain the action of p65moving to cell nucleus campared to placebogroup (P<0.05). In HIS, RGZ+imidapril-treated group was significantly lower ascompared to placebo group (3.38±1.60vs5.13±1.25, P<0.05).The expression of atrogin-1/MAFbx and MuRF-1: Both atrogin-1/MAFbx andMuRF1encoded proteins that were E3ubiquitin ligases. E3ligases were enzymesresponsible for the substrate specificity of ubiquitin conjugation, and, therefore, thesemolecules were essential for proteasome-mediated protein degradation. Alltumor-bearing mice were significant higher than healthy control mice in theexpression of atrogin-1and MuRF-1. About the the expression of atrogin-1, RGZ,imidapril and RGZ+imidapril-treated groups showed a significant decrease by63%,30%,65%respectively (all, P<0.05as compared to placebo group). About the theexpression of MuRF-1, RGZ and RGZ+imidapril-treated groups showed a significantdecrease by33%,24%respectively (all, P<0.05as compared to placebo group); andtreatment with imidapril group increased by8%as compared to placebo group,however this was not statistically significant.Conclusion:1. Cancer cachexia mice had a body weight losing and a metabolic disorder. The interaction of proinflammatory cytokines, tumor-derived factors, the activating of NF-κB and Two genes atrogin-1/MAFbx with MuRF1may induces cachexia.2. Mice treated with RGZ+imidapril had significantly better than the placebo groupand all other treatment groups.