Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice

Abstract

More than 50% of patients with advanced stages of colon cancer suffer from progressive loss of skeletal muscle, called cachexia, resulting in reduced quality of life and shortened survival. It is becoming evident that reactive oxygen species (ROS) regulate pathways controlling skeletal muscle atrophy. Herein we tested the hypothesis that antioxidant supplementation could prevent skeletal muscle atrophy in a model of cachectic Colon 26 (C26) tumor-bearing mice. Seven-week-old BALB/c mice were subcutaneously inoculated with colon 26 (C26) cancer cells or PBS. Then C26-mice were daily gavaged during 22 days either with PBS (vehicle) or an antioxidant cocktail whose composition is close to that of commercial dietary antioxidant supplements (rich in catechins, quercetin and vitamin C). We found that antioxidants enhanced weight loss and caused premature death of mice. Antioxidants supplementation failed to prevent (i) the increase in plasma TNF-α levels and systemic oxidative damage, (ii) skeletal muscle atrophy and (iii) activation of the ubiquitin-proteasome system (MuRF-1, MAFbx and polyubiquitinated proteins). Accordingly, immunohistological staining for Ki-67 and the expression of cell cycle inhibitors demonstrated that tumor of supplemented mice developed faster with a concomitant decrease in oxidative damage. Previous studies have shown that the use of catechins and quercetin separately can improve the musculoskeletal function in cachectic animals. However, our results indicate that the combination of these antioxidants reduced survival and enhanced cachexia in C26-mice.

The Janus‐Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

“…Cachectic C26 mice exhibited a net augmentation in protein carbonyls and 4-HNE content within plasma, without any change in skeletal muscle. The absence of muscular oxidative damage in our model could be attributed to the upregulation of catalase expression, exclusively, in atrophied muscles [17]. Other experimental studies have also shown that mice bearing Walker 256 and MAC13/16 tumors developed cardiac cachexia in response to DNA and/or protein oxidative damage in heart tissues [20, 36].…”

“…A previous study demonstrated that nuclear factor- κ B (NF- κ B) was rapidly activated by H 2 O 2 , following treatment of C2C12 muscle cells with TNF- α [10]. We have also shown that circulating levels of TNF- α were increased in cachectic mice bearing colon tumor and coincided with a greater phosphorylation of the NF- κ B (p65) subunit, within atrophied muscles [17]. The nuclear accumulation of NF- κ B promotes the transcriptional upregulation of muscle-specific E3 ubiquitin-ligases, MuRF-1 and MAFbx , which in turn tag myofibrillar proteins (i.e., myosin) with polyubiquitin chains for proteasome processing [52].…”

“…Unfortunately, the obtained results were not always positives but sometimes without any significant effect or even deleterious [12–19]. Indeed, if the use of antioxidants appears to be complicated in cancer, it could be even more problematical in cancer cachexia given the intricate tissue crosstalk and the disruption of redox balance that takes place in many organs, including skeletal muscle, heart, liver, and blood [17, 20, 21]. In other words, high levels of ROS could be present at different sites, at the same time, and exert distinct roles in an organ-dependent manner.…”

“…In other words, high levels of ROS could be present at different sites, at the same time, and exert distinct roles in an organ-dependent manner. For example, the inhibition of ROS could be beneficial in skeletal muscle to reduce the magnitude of atrophy but deleterious within tumor as this may accelerate proliferation and growth [17, 22]. This multiorgan presence of ROS confers to cachexia an overelaborate nature and, thus, makes the intervention with antioxidants more perplexing.…”

Nutraceuticals: The New Generation Therapeutics

“…Vitamin E may help prevent CIPN. l-glutamine, goshajinkigan, and omega-3 are also promising in the prevention of the effects of CIPN [7].…”