Dietary garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in rats
Introduction
The incidence and the mortality of oral cancer, which is one of the important public health issues, have increased over the past decades in Europe [1] and in the United States [2]. Although Japan has one of the lowest incidences of oral, lip, and pharyngeal cancers in the world [3], the patients with these malignancies have recently been increasing [4]. Despite recent advances in surgery, chemotherapy, and radiotherapy, the survival of patients with oral carcinoma remains poor [1], [2]. Furthermore, patients with oral cancer have an increased incidence of developing second primary tumors of the oral cavity [5], [6]. The variation in the incidence of oral cancer in the world is related to exposure to known etiologic agents. It is generally believed that oral carcinomas are caused predominantly by chemical carcinogens, although there is evidence implicating viral, fungal, and physical stimuli in the genesis of some oral neoplasms. Tobacco and alcohol use and the combination of exposure to both are the major risk factors in the development of oral cancer and simultaneous or subsequent second primary cancers [5], [6], [7], [8], [9], [10]. One promising approach to reduce the incidence and improve the prognosis of this malignancy is chemoprevention [11]. Dietary factors also play an important role in human health and in the development of certain chronic diseases including cancer [12], [13]. Some foods contain antitumor compounds as well as mutagens and/or carcinogens [14]. Such compounds are candidates for chemopreventive agents against cancer development [15].
A polyisoprenylated benzophenone garcinol (Fig. 1, also named camboginol [16] is present in Guttiferae (Garcinia indica, Garcinia huillkensis and Garcinia cambogia). Garcinia is a rich source of secondary metabolites including xanthone and flavanoids. In India the dried fruit rind of G. indica (‘Kokum’) is used as a garnish for curry and in some of the folklore medicine and it contains a yellow pigment of garcinol (2–3%, w/w). Garcinol is known to have the same antioxidant property as other chemopreventive agents [17]. We previously reported a possible chemopreventive ability of garcinol in chemically induced colonic preneoplastic lesions in rats [18]. In addition, we demonstrated that garcinol suppresses expression of cyclooxygenase (COX)-2 proteins [18]. Overexpression of COX-2 and elevation of COX-2-mediated prostaglandin (PG) E2 biosynthesis are involved carcinogenesis in certain organs including oral cavity [19], [20], [21].
One of the suitable animal models for field cancerization and for detecting cancer chemopreventive agents is 4-nitroquinoline l-oxide (4-NQO)-induced rat oral carcinogenesis model [22]. 4-NQO, a water-soluble quinoline derivative, produces a spectrum of preneoplastic and neoplastic lesions in the oral cavity, especially tongue, of rats following 4-NQO application in drinking water. Oral lesions produced by 4-NQO are comparable to human lesions, because many ulcerated and endophytic or exophytic tongue tumors and dysplasia develop when 4-NQO in the drinking water is given to rats or 4-NQO is applied topically to the oral mucosa [23]. Using 4-NQO-induced rat oral carcinogenesis model, we have reported several candidates for chemopreventive agents against oral malignancy [22].
In the current study, possible inhibitory effects of dietary exposure of garcinol during the initiation or post-initiation stages on 4-NQO-induced oral carcinogenesis were investigated in male F344 rats. In addition, the effect of the compound on cell proliferation activity in the tongue was assessed by measuring 5-bromodeoxyuridine (BrdU)-labeling index and cyclin D1-positive cells. The effect of the expression of COX-2 was slso immunohistochemically determined in the tongue lesions induced by 4-NQO.
Section snippets
Animals, diets, test chemical, and carcinogen
Male F344 rats, 4 weeks old, were purchased from Charles River Japan (Kanagawa, Japan). After a 2-week quarantine, they were maintained in a holding room under the controlled conditions of a 12 h light/dark cycle, 23±2 °C room temperature, and 50±10% relative humidity. The rats were randomized into experimental and control groups. They were housed three or four to a wire cage. Food and water were available ad libitum. Powdered CE-2 (CLEA Japan, Inc., Tokyo, Japan) was used as a basal diet during
General observations
Animals in groups 1–7 tolerated well the oral administration of 4-NQO and/or garcinol. Mean daily food intakes (16.4 g/rat in group 1, 15.8 g/rat in group 2, 16.5 g/rat in group 3, 16.2 g/rat in group 4, 17.0 g/rat in group 5, 16.6 g/rat in group 6, and 16.8 g/rat in group 7) were insignificant among the groups. Mean daily intake of garcinol/rat was calculated with 1.58 mg in group 2, 8.25 mg in group 3, 1.62 mg in group 4, 8.75 mg in group 5, and 8.30 mg in group 6. There were no significant differences
Discussion
The results in the current study indicated that feeding with garcinol during either the initiation or post-initiation phase effectively suppressed 4-NQO-induced oral carcinogenesis. The inhibition by garcinol might be in a dose-dependent manner. Interestingly no SCC was developed in rats given the higher dose (500 ppm) of garcinol after 4-NQO exposure. The mean intake of 500 ppm garcinol (8.75 mg/day/rat), which caused 100% inhibition of tongue carcioma when fed during the promotion phase of
Acknowledgements
This research was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare in Japan; by a Grant-in-Aid for Cancer Research (13–15) from the Ministry of Health, Labour and Welfare in Japan; by a Grant-in-Aid (no. 15592007) from the Ministry of Education, Science, Sports and Culture in Japan; and by Grants (H2004-6 and C2004-4) from Kanazawa Medical University. The authors thank Ms Kyoko Takahashi,
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