Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats.
OBJECTIVE
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 microg/mL (0-698 microM for indomethacin, and 0-147 microM 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.
Bonin
Antonio M
AM
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Yáñez
Jaime A
JA
Fukuda
Chie
C
Teng
Xiao Wei
XW
Dillon
Carolyn T
CT
Hambley
Trevor W
TW
Lay
Peter A
PA
Davies
Neal M
NM
D000118:Acetylglucosaminidase / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use*; D001397:Azoxymethane; D002273:Carcinogens; D002432:Cecum / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D003300:Copper / Q000009:adverse effects* / Q000627:therapeutic use*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004338:Drug Combinations; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000473:pathology; D004573:Electrolytes / Q000652:urine; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006242:Haptoglobins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D007213:Indomethacin / Q000009:adverse effects* / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D004272:DNA, Mitochondrial; D004338:Drug Combinations; D004573:Electrolytes; D006242:Haptoglobins; D006454:Hemoglobins; D003300:Copper; D000118:Acetylglucosaminidase; D001397:Azoxymethane; D007213:Indomethacin