Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia

Abstract

Cachexia is a common co-morbidity in cancer occurring in up to 80% of patients depending on the type of cancer. Uric acid (UA), the end-product of the purine metabolism, is elevated in cachexia due to tissue wasting and upregulated xanthine oxidase (XO) activity. High serum UA levels indicate increased XO-dependent production of oxygen free radicals (reactive oxygen species; ROS) and correlate with metabolic illness and poor survival. We hypothesized that XO-inhibition might reduce inflammatory signals accounting for tissue wasting and improve survival in experimental cancer cachexia. Animals were inoculated intraperitoneally with AH-130 hepatoma cells and treated with two XO-inhibitors: allopurinol [Allo, low (LD) and high dose (HD) 4 and 40 mg/kg/d] and its more effective active metabolite oxypurinol (Oxy, 4 and 40 mg/kg/d) or placebo for 15 days. Weight loss and tissue wasting of both fat and lean tissue (assessed by NMR-scanning) was reduced by both LD and HD Allo and LD-Oxy, but not by HDOxy. A robust induction of XO-activity for generation of reactive oxygen species was seen in the placebo group (assessed by electron paramagnetic spectroscopy), which was reduced by XO-inhibition. Increased ROS induced cytokine signaling, proteolytic activity and tissue degradation were all attenuated by XO inhibition. Survival was significantly and dose dependently improved. Food intake and spontaneous locomotor activity were higher, indicating a higher quality of life. Inhibition of XO can reduce tissue wasting and improve survival in cancer cachexia and clearly clinical studies are needed.

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

“…Some authors have demonstrated a relationship between XO action and increased oxidative stress, declining muscle mass and strength in aged animals [80,81] . Springer et al [82,83] showed that the inhibition of XO reduced levels of oxidative stress, maintaining muscle mass and reducing cachexia in cachectic animals. In another study with immobilized animals, Kondo et al [84] showed an increase of 2 or 3 times the XO activity in the soleus muscle.…”

Body Weight Loss, Tissue Wasting and Shortened Lifespan in Late Middle-aged Mice on Imbalanced Essential/Non-essential Amino Acids Diet

“…Besides dramatic weight loss, no other signs of suffering, such as hypothermia, apathy, persisting staggering, bleeding, persisting diarrhea, labored breathing, cyanosis, complete lack of food intake or dehydration [19], were reported. However, to avoid further discomfort and in accordance with ethical standards, all animals belonging to these two feeding groups were euthanized.…”

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

“…In the experimental models of cancer cachexia, rats bearing Yoshida tumor and mice bearing MAC16 adenocarcinoma, the activity of XO was elevated in skeletal and/or cardiac muscles and correlated with an increase in muscle oxidative damage [20, 76–78]. Although XO is not usually present at high levels within skeletal muscle, the hyperactivation of XO during cachexia could be explained by an increase in the cleavage of XDH to XO [76].…”

“…In the experimental models of cancer cachexia, rats bearing Yoshida tumor and mice bearing MAC16 adenocarcinoma, the activity of XO was elevated in skeletal and/or cardiac muscles and correlated with an increase in muscle oxidative damage [20, 76–78]. Although XO is not usually present at high levels within skeletal muscle, the hyperactivation of XO during cachexia could be explained by an increase in the cleavage of XDH to XO [76]. The small number of studies that addressed the role of XO in cachexia-induced muscle wasting demonstrated that targeting XO with selective inhibitors such as allopurinol (4 and 40 mg/kg/day), oxypurinol (4 and 40 mg/kg/day), and febuxostat (5 mg/kg/day) can reduce body weight loss and skeletal muscle/heart atrophy [76–78].…”