Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone.
Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3- to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-delta) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-delta.
Roy
H K
HK
Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-2000, USA.
Karolski
W J
WJ
Ratashak
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002074:Butanones / Q000627:therapeutic use*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009092:Mucous Membrane / Q000378:metabolism; D000077430:Nabumetone; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D002074:Butanones; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077430:Nabumetone