Chemopreventive Effect of a Xanthine Oxidase Inhibitor, 1′‐Acetoxychavicol Acetate, on Rat Oral Carcinogenesis

Abstract

The effect of a xanthine oxidase inhibitor, 1′‐acetoxychavicol acetate (ACA), on 4‐nitroquinoline 1‐oxide (4‐NQO)‐induced oral carcinogenesis was investigated in male F344 rats. All rats except those in the ACA‐alone and untreated groups were given 4‐NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Starting 1 week before the 4‐NQO exposure, animals were fed diet containing 100 ppm or 500 ppm ACA for 10 weeks, followed by the basal diet without ACA for 22 weeks. Other groups were fed the diet containing ACA at 100 ppm or 500 ppm for 22 weeks, starting 1 week after the cessation of 4‐NQO exposure. The remaining groups consisted of rats given 500 ppm ACA alone or untreated rats. At the termination of the experiment (32 weeks), the incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated in terms of 5‐bromodeoxyuridine (BrdU)‐labeling index and by morphometric analysis of silver‐stained nucleolar organizer regions’ protein (AgNORs) were compared among the groups. Feeding of ACA at the two doses during initiation or postinitiation significantly decreased the development of tongue carcinoma (93–100% reduction, P< 0.001) and preneoplasia (43–50% reduction for hyperplasia and 34–48% reduction for dysplasia, P<0.05). There were no such lesions in rats fed ACA alone or those in the untreated control group. The number of AgNORs per cell nucleus was significantly decreased by feeding of ACA at a high dose (500 ppm) (29% inhibition, P<0.05). The BrdU‐labeling index was also reduced by dietary administration of ACA (23–32% inhibition, P<0.01). In addition, ACA feeding reduced tongue polyamine levels (35–40% inhibition, P<0.05). These results indicate that ACA inhibited rat oral carcinogenesis, and such inhibition might be related to suppression of cell proliferation in the oral mucosa by the xanthine oxidase inhibitor.

Suppression of N‐Nitrosomethylbenzylamine‐induced Rat Esophageal Tumorigenesis by Dietary Feeding of 1′‐Acetoxychavicol Acetate

“…26) In a survey of anti-tumor promoters in edible plants of Thailand, this agent was found to inhibit tumor promoter-induced Epstein-Barr virus activation in vitro. 27) In addition, we have found a strong cancer chemopreventive effect of ACA on 4-NQO-induced oral carcinogenesis 28) and AOMinduced colon adenocarcinoma in rats. 29) This evidence led us to investigate the modifying effects of ACA on experimental esophageal carcinogenesis.…”

Identification of a Novel Blocker of IκBα Kinase That Enhances Cellular Apoptosis and Inhibits Cellular Invasion through Suppression of NF-κB-Regulated Gene Products

“…One of these, 1Ј-acetoxychavicol acetate (ACA), 3 derived from the rhizomes of a subtropical ginger, Languas galanga Stuntz (Zingiberaceae), has been shown to exhibit antitumor properties against a wide variety of cancers (2)(3)(4)(5)(6)(7)(8)(9)(10). For instance, ACA has been shown to inhibit phorbol ester-induced skin tumor promotion (8), azoxymethane-induced colonic aberrant crypt foci (7), estrogen-related endometrial carcinogenesis (6), hepatic focal lesions (5), rat oral carcinogenesis (4), and N-nitrosomethylbenzylamineinduced rat esophageal tumorigenesis (3). How ACA suppresses tumorigenesis is not well understood.…”

“…Protein tyrosine phosphorylation and reduction of cellular sulfhydryl groups have been implicated in ACA-induced apoptosis (12). Still other reports have indicated that ACA has antioxidant and anti-inflammatory activities (13,14), inhibits xanthine oxidase (4), and suppresses inducible NO synthase gene expression (14). How ACA mediates antitumor activities is not well understood.…”

Modifying Effects of 1'-Acetoxychavicol Acetate (ACA) and the Novel Synthetic Retinoids Re-80, Am-580 and Am-55P in a Two-Stage Carcinogenesis Model in Female Rats

“…ACA was reported to have a cancer chemopreventive effect at 100 ppm or 500 ppm in diet, and the mean body weights of 500 ppm groups were significantly smaller than that of each control group (Kagechika et al, 1989b;Ohnishi et al, 1996;Tanaka et al, 1997a).…”

“…In non-initiation groups, tumors were not observed in any organ. DISCUSSION ACA has been found to be a potential inhibitor of tumorpromotion in an in vitro Epstein-Barr virus activation test Re-80 1 18 10 (55.6) 2.0 ± 3.1 6.8 ± 18.0 * 12 (66.7) 1.7 ± 1.9 4.2 ± 11.7 15 (83.3) 3.7 ± 3.9 5.5 ± 15.4 Re-80 0.4 18 6 (33.3) 0.9 ± 1.9 2.3 ± 3.4 * 9 (50.0) 1.6 ± 3.3 8.7 ± 18.5 12 (66.7) 2.4 ± 4.0 6.4 ± 15.1 Am-580 20 18 3 (16.7) 0.2 ± 0.4 0.2 ± 0.1 15 (83.3) 3.1 ± 2.6 9.9 ± 5.3 15 (83.3) 3.3 ± 2.8 4.4 ± 5.2 Am-580 5 18 8 (44.4) 0.7 ± 1.0 0.4 ± 0.4 15 (83.3) 3.3 ± 3.1 5.5 ± 5.3 16 (88.9) 4.1 ± 3.8 4.6 ± 8.5 Am-55P 20 18 7 (38.9) 1.2 ± 2.6 6.9 ± 17.1 8 (44.4) 2.2 ± 3.6 2.2 ± 7.7 12 (66.7) 3.4 ± 4.8 3.8 ± 10.8 ACA 100 18 12 (66.7) 1.9 ± 2.6 0.7 ± 0.8 10 (55.6) 1.4 ± 1.9 6.1 ± 11.5 16 (88.9) 3.3 ± 3.0 2.9 ± 8.3 All-trans-retinoic acid 10 17 10 (58.8) 1.4 ± 2.1 0.5 ± 0.9 10 (58.8) 1.1 ± 1.4 3.1 ± 7.5 14 (82.4) 2.5 ± 2.6 1. for screening of edible plants from Thailand (Kondo et al, 1993;Murakami et al, 1995), and ACA showed chemopreventive or anti-tumor promotion activities in vivo studies in rats or mice treated with chemical carcinogens (Tanaka and Mori, 1995;Murakami et al, 1996;Ohnishi et al, 1996;Nakamura et al, 1998;Tanaka et al, 1997aTanaka et al, , 1997b. ACA inhibits xanthine oxidase activity and nitric oxide production (Noro et al, 1988;Ohata et al, 1998) involved in tumorigenesis (Pence and Reiners, 1987;Cerutti, 1994 chromosomal change, and activation of cytoplasmic signal transduction pathways related to cell growth (Cerutti, 1994).…”