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Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats

Journal Article


Abstract


  • 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. © 2009 Springer-Verlag.

Authors


  •   Bonin, Antonio M. (external author)
  •   Yanez, Jaime A. (external author)
  •   Fukuda, Chie (external author)
  •   Teng, Xiao Wei (external author)
  •   Dillon, Carolyn T.
  •   Hambley, Trevor W. (external author)
  •   Lay, Peter A. (external author)
  •   Davies, Neal M. (external author)

Publication Date


  • 2010

Citation


  • Bonin, A. M., Yanez, J. A., Fukuda, C., Teng, X. Wei., Dillon, C. T., Hambley, T. W., Lay, P. A. & Davies, N. M. (2010). Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats. Cancer Chemotherapy and Pharmacology, 66 (4), 755-764.

Scopus Eid


  • 2-s2.0-77955904651

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3843

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 755

End Page


  • 764

Volume


  • 66

Issue


  • 4

Abstract


  • 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. © 2009 Springer-Verlag.

Authors


  •   Bonin, Antonio M. (external author)
  •   Yanez, Jaime A. (external author)
  •   Fukuda, Chie (external author)
  •   Teng, Xiao Wei (external author)
  •   Dillon, Carolyn T.
  •   Hambley, Trevor W. (external author)
  •   Lay, Peter A. (external author)
  •   Davies, Neal M. (external author)

Publication Date


  • 2010

Citation


  • Bonin, A. M., Yanez, J. A., Fukuda, C., Teng, X. Wei., Dillon, C. T., Hambley, T. W., Lay, P. A. & Davies, N. M. (2010). Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats. Cancer Chemotherapy and Pharmacology, 66 (4), 755-764.

Scopus Eid


  • 2-s2.0-77955904651

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3843

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 755

End Page


  • 764

Volume


  • 66

Issue


  • 4