Eicosapentaenoic acid (EPA)-containing nutrition supplements have been clinically shown to attenuate weight loss and improve quality of life in patients with cancer. This study examined effects of known anticachectic agents, green tea extract (GTE) or curcumin (C3), alone or in combination with EPA on muscle wasting markers and tumor growth. In fully differentiated murine C2C12 myotubes, TNF-α and proteolysis-inducing factor (PIF) were used to mimic cancer cachexia. GTE and C3 alone effectively attenuated TNF-α- and PIF-induced protein degradation, measured by [2,6-3H] Phe release assay, in a dose response manner. In PIF model, EPA (50 µM) reduced protein degradation from 119% to 109%; this was further reduced to negative control levels by combining GTE (10 µg/mL) or C3 (10 µg/ml) with EPA. PIF-induced expression of proteasome 19S, 20S subunits and E3 Ubiquitin (Ub)-ligases of the ubiquitin proteasome proteolytic pathway (UPPP) was decreased by GTE, C3 or in combination with EPA. Similar results were also observed in TNF-α model. Protein synthesis as measured by [4-3H]Phe incorporation was increased by 9% by the combinations over EPA alone in the PIF model only. In nude mouse xenograft models of human colon and lung cancer (n=12/group), EPA (400 mg/kg), GTE (100 mg/kg), C3 (200 mg/kg), alone or in combination, given by oral gavage daily for 28 days, showed no effect on tumor growth. The % changes in mean body weight from baseline were similar between groups. In summary, combining EPA with GTE or C3 enhances its ability to attenuate muscle protein loss. This has implication for future nutritional interventions for cancer-induced cachexia. Combination of these agents can be safely administered in tumor-bearing mice. Funded by Abbott Nutrition.