Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats
Purpose: To evaluate, for the first time, the efficacy of copper–indomethacin in the inhibition of aberrant crypt foci formation using the azoxymethane-induced adenocarcinoma model, to examine cell viability in the HCT-116 colorectal cancer cell line, gastrointestinal permeability, mitochondrial oxidative damage, and renal toxicity in rat models. Methods: Azoxymethane-induced adenocarcinoma rats were dosed with indomethacin and copper–indomethacin for 28 days and aberrant crypt foci were evaluated. HCT-116 colorectal cancer cells were exposed to indomethacin and copper–indomethacin at 0–250 μg/mL (0–698 μM for indomethacin, and 0–147 μM for copper–indomethacin), and cell viability was measured. Acute gastrointestinal toxicity was measured using gastrointestinal permeability markers, gastrointestinal ulceration and bleeding, and measurement of an acute-phase protein haptoglobin. Effects of acute and chronic administration of indomethacin and copper–indomethacin on urinary electrolyte concentrations were examined. Results: Both indomethacin and copper–indomethacin resulted in a significant reduction in aberrant crypt foci in azoxymethane-treated rats. In parallel, high concentrations of indomethacin and copper–indomethacin also reduced cell viability in HCT-116 colorectal cancer cells. However, copper–indomethacin was considerably safer in all measures of gastrointestinal toxicity compared to indomethacin. In addition, indomethacin reduced urinary electrolytes at an ulcerogenic dose of 10 mg/kg acutely and chronically at 3.0 mg/kg for 28 days, whereas copper–indomethacin at equimolar doses of indomethacin affected urine electrolytes after acute dosing but not after chronic dosing for 28 days. Conclusions: Copper–indomethacin has both gastrointestinal and renal sparing properties while maintaining efficacy in experimental adenocarcinoma.