Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate.
In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.
Tanaka
T
T
Department of Pathology, Gifu University School of Medicine.
Kawabata
K
K
Kakumoto
M
M
Makita
H
H
Matsunaga
K
K
Mori
H
H
Satoh
K
K
Hara
A
A
Murakami
A
A
Koshimizu
K
K
Ohigashi
H
H
D000821:Animal Feed; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity*; D001592:Benzyl Alcohols; D014408:Biomarkers, Tumor / Q000032:analysis; D002273:Carcinogens / Q000633:toxicity*; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000032:analysis / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis / Q000096:biosynthesis; D009955:Ornithine Decarboxylase / Q000032:analysis / Q000096:biosynthesis; D011073:Polyamines / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013729:Terpenes / Q000494:pharmacology*; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D016588:Anticarcinogenic Agents; D001592:Benzyl Alcohols; D014408:Biomarkers, Tumor; D002273:Carcinogens; D004791:Enzyme Inhibitors; D011073:Polyamines; D013729:Terpenes; D014969:Xanthine Oxidase; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D009955:Ornithine Decarboxylase; D001397:Azoxymethane; C047948:1'-acetoxychavicol acetate