Abstract
Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro- and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P<0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P<0.05). EPA (18.2±3.2 pg/ml) and combination (18.4±3.7 pg/ml) groups had significantly higher 8-OH-dG levels than the control group (12.9±1.4 pg/ml, P≤0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P≤0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P≤0.05). Activity of total SOD was higher in the oxypurinol group (32.2±1.5 U/ml) compared to control (27.0±1.3 U/ml, P<0.01), GPx activity was lower in the EPA group (8.76±2.0 U/ml) compared to control (14.0±1.9 U/ml, P<0.05), and catalase activity was lower in the combination group (14.4±2.8 U/ml) compared to control (20.9±2.0 U/ml, P<0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia.
Highlights
Many forms of cancer present with a complex metabolic profile characterized by loss of lean body mass and adipose tissue, known as cancer cachexia
There was no statistical difference in size of final tumor between eicosapentaenoic acid (EPA) (338667 mm3) and control (308628 mm3) groups, while oxypurinol (489678 mm3) and combination (515641 mm3) treatment groups showed increased final tumor size compared to both control (P,0.01) and EPA groups (P,0.05)
The EPA group increased in body weight during the pre-cachectic phase, before weight stabilization, and maintained this pre-cachectic state until day 22, when weights started to decline, with significant weight-loss from day 25
Summary
Many forms of cancer present with a complex metabolic profile characterized by loss of lean body mass and adipose tissue, known as cancer cachexia. Patients suffering cachexia may lose up to 30% of their original body weight, with 45% of patients losing more than 10% of their original weight over disease progression [4]. Oxidative stress may play an integral role in cancer cachexia, with evidence of oxidative damage and high levels of reactive oxygen species (ROS) found in many cancer states [5]. The role of ROS in the development of cancer cachexia, and the mechanisms that cause the disease remain largely unknown, despite several advances in identifying circulatory factors and pathways that are active. A shift in the balance between reactive oxidants and antioxidants can induce a state of oxidative stress that is detrimental to the cell, and may be one of the key factors in the development of cachexia
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