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Metabolomic derangements in cancer cachexia are modulated by leucine-rich diet in Walker 256 tumour-bearing rats.

Abstract

Background: Cachexia is one of the most important causes of many cancer-related deaths. Cancer-cachexia is a complex metabolic syndrome characterised by involuntary weight loss, mostly due to the skeletal muscle tissue wasting. Leucine supplementation has been used to minimise muscle tissue depletion due to its ability to stimulate protein synthesis pathways and inhibit protein degradation. Even so, there have been few studies that have investigated the influence of this nutritional supplementation on tumour tissue. The aim of this study was to analyse the metabolomic derangements in serum and tumour tissue in Walker 256 tumour-bearing rats under the modulatory effect of a leucine-rich diet.Material and Methods: Female Wistar rats were distributed into four experimental groups: C, control group; W, Walker 256 tumour-bearing group; L, leucine control group; LW, Walker 256 tumour-bearing group. We assessed serum and tumour tissue metabolomic profile, tumour proliferation and protein synthesis pathways.Results: Among the 58 serum metabolites, we found 12 metabolites changed in W group and 23 metabolites changed in LW group, suggested a different impact on metabolic pathways between both tumour-bearing groups. The tumour-bearing rats (W) increased some of their metabolic pathways via related to source energy provision that diverted many nutrients to tumour cell growth. The LW tumour group, despite increased tumour cell activity (higher Ki-67 and mTOR tumour tissue expressions), exhibited no difference in tumour mass growth, suggesting the majority of nutrients were diverted to host maintenance as the valine, leucine and isoleucine synthesis and degradation and also synthesis and degradation of ketonic bodies were the mainly metabolic pathways activated in LW group.Conclusions: The tumour growth led to some biochemical and molecular changes including the metabolites profile, which some of them are specifics of the tumour effects on catabolic state. Leucine-rich diet modulated some alterations in tumour-bearing rats, as the increase of ketone body metabolism, which could not be use by neoplastic cells. The use of leucine rich-diet as an alternative co-adjuvant therapy is being widely studied as a target of cachexia, due to the capacity of leucine in increase muscle protein synthesis and inhibiting protein degradation. The modulation of this nutritional supplementation needs to be more investigated as it leads to metabolic derangements without increasing the tumour evolution. (AU)