Role of Combination Treatment of Aspirin and Zinc in DMH-DSS-induced Colon Inflammation, Oxidative Stress and Tumour Progression in Male BALB/c Mice

Colitis-associated colorectal cancer serves as a prototype of inflammation-associated cancers which is linked with repeated cycles of inflammation and DNA repair deficits. Several preclinical and clinical data reported that aspirin has a chemo-preventive effect in colorectal cancer and is associated with dose-dependent side effects. Furthermore, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in the combined administration of aspirin and zinc-mediated protection against colitis-associated colorectal cancer deserves further investigation. For the induction of colitis-associated colorectal cancer, male BALB/c mice were administered 1,2-dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) were administered for 8 weeks. Combination of aspirin and zinc as intervention significantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various inflammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase-2 (COX-2) and interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression significantly decreased, and antioxidant enzymes nuclear factor erythroid 2-related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) significantly increased as evaluated by immunohistochemistry and western blot analysis.