Eicosapentaenoic acid supplementation reduces tumor volume and attenuates cachexia in a rat model of progressive non-metastasizing malignancy.

Abstract

Eicosapentaenoic acid (EPA) has been shown to have anti-inflammatory and tumor growth inhibitory effects clinically and experimentally; evidence also supports the role of EPA in attenuating cancer-associated weight loss, but the mechanisms of these effects remain to be defined. As the liver plays a central role in modulating nutritional status and the cachexia syndrome, we examined the liver and nutritional parameters indicative of cachexia along with the tumor volume in response to oral EPA supplementation in a rat model of progressive non-metastasizing malignancy. Fischer 344 rats implanted with the methylcholanthrene-induced fibrosarcoma (MCA) were trained to meal-feed with access to food from 8:00 PM to 8:00 AM and water ad libitum. On day 13, rats were randomly divided into 3 study groups: (1) 5.0 g/kg per day EPA plus 10 IU vitamin E/g fat, (2) 5.0 g/kg per day corn oil plus 10 IU vitamin E/g fat, and (3) 5.0 g/kg per day saline plus 10 IU vitamin E/g saline. The treatment was delivered via oral gavage twice daily. The animals were killed on day 29, and serum plus tissues (ie, liver and lung) were collected and frozen for analysis. Parameters evaluated include the following: tumor volume, weight loss, liver weight, total liver protein, liver lipid content, serum albumin content, and macrophage inflammatory protein-2 (MIP-2) levels. EPA-treated rats showed a reduction in tumor volume compared with corn oil (25% reduction, p < .01) and saline (33% reduction, p < .01) animals. EPA rats also demonstrated increased liver weight (p < .01) and total liver protein levels (p < .03) over saline-treated animals. EPA- and corn oil-treated rats received more calories than the saline group because of the dietary fat treatments (p < .01) and had elevated lipid content in their livers (p = .05 and p = .04, respectively) compared with saline rats. Serum albumin (a marker of liver function) and MIP-2 levels (a marker of the hepatic acute phase response) were not different between treatment groups. EPA supplementation resulted in a dramatic reduction of tumor volume and mild improvements in weight maintenance. In addition, EPA-treated animals demonstrated increased total liver protein and serum protein levels. Regression analyses showed that the weight and protein differences between treatment groups were not correlated with individual tumor volumes. The increase in liver and serum protein was not explained by differences in albumin or MIP-2. We conclude that the tumor growth inhibitory effects and anticachexiogenic effects of EPA are independent phenomena, and the effects on cachexia may be related to increased levels of undefined protein(s) in the liver and serum. To our knowledge, this is the first study to demonstrate the effects of EPA in the MCA fibrosarcoma model and is also novel in its evaluation of EPA as an anticachexiogenic therapy in progressive non-metastasizing malignancy. Further studies may identify the protein(s) elevated in the liver and the mechanisms for the development of EPA nutritional therapies for the treatment of progressive malignancies.