title: Eicosapentaenoic acid and oxypurinol in the treatment of muscle wasting in a mouse model of cancer cachexia.
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.
authors.affiliation: School of Medicine, Deakin University, Waurn Ponds, Australia.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Vaughan
authors.forename: Melanie
authors.initials: M
authors.lastname: Sullivan-Gunn
authors.forename: Edward
authors.initials: E
authors.lastname: Hinch
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lewandowski
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000188:drug therapy; D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D015118:Eicosapentaenoic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000209:etiology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000150:complications* / Q000188:drug therapy; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress; D010117:Oxypurinol / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000378:metabolism; D047368:Tumor Burden; D015431:Weight Loss / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015118:Eicosapentaenoic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D010117:Oxypurinol