Comparing The Effects Of Nexrutine And Exercise In Modulating The Pathophysiology Of Cachexia In Treatment Naïve Prostate Cancer Mouse Model

Abstract

Oncologists encourage nutritional and physical interventions to improve outcomes in cancer patients with cachexia; however, it is inconclusive how these interventions affects the pathophysiology of cachexia. PURPOSE: To compare the effects of Nexrutine® (Nex; a natural bark extract of the Amur cork tree) and exercise in modulating the pathophysiology associated with cachexia in treatment naive transgenic adenocarcinoma of mouse prostate (TRAMP) model. METHODS: Forty-five, 10-week old male TRAMP mice were randomized to control (Con), Nex (600 mg/kg pelleted into chow) or exercise (Ex; voluntary wheel running). At 4, 8, 12 and 20 weeks, gastrocnemius muscle was collected to quantify intramuscular IGF-1, myostatin, TNF-α, proteolysis-inducing factor (PIF) and ubiquitin (Ub). An ANOVA with Tukey’s post hoc test was done with significance set at p<0.05. RESULTS: Analysis of gastrocnemius mass revealed significant group differences (F=4.159, p=0.02) with both Nex and Ex groups having greater mass compared to Con (p<0.05). A treatment response was observed for myostatin (F=4.762; p=0.01), PIF (F= 8.633, p=0.001) and Ub (F=19.55, p<0.001). Specifically, Ex mice had significantly lower concentrations of myostatin, PIF and Ub compared to Con (p<0.01). Group comparisons at 20 weeks showed significantly lower concentrations of PIF (F= 22.85, p<0.001) with Ex (p<0.001) and Nex (p=0.03) significantly lowering PIF concentrations compared to Con. Time point comparisons for Ub revealed significant differences at weeks 4 (F=32.35, p<0.001) and week 8 (F=16.24,p=0.002), respectively, with Ex mice having significantly lower concentrations of Ub compared to Con mice (p=0.004) at both time points. CONCLUSION: The results of this study suggest that Nex and Ex similarly maintain muscle mass in treatment naïve TRAMP mice by reducing tumor specific cachectic protein PIF. Exercise was capable of reducing downstream Ub; however, the mechanisms by which Nex elicits a protective effect require further study.