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* Department of Endoscopy, Hiroshima University Hospital, Minami-ku, Hiroshima 734–8551, Japan, Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki 701–0192, Japan, ** Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734–8551, Japan, Health Service Center, Hiroshima University, Higashihiroshima 739–8521, Japan, Onomichi General Hospital, Onomichi 722–8508, Japan, Wakunaga Pharmaceutical Co., Ltd., Akitakata 739–1195, Japan, and # Wakunaga of America Co., Ltd., Mission Viejo, CA 92691
3 To whom correspondence should be addressed. E-mail: colon{at}hiroshima-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • garlic • S-allylcysteine • colorectal adenoma • cancer prevention
Foods with cancer-prevention potential are used in many epidemiological and animal studies and garlic is considered one such food (1). Buiatti et al. (2), in a case-control study with 1,016 histologically confirmed gastric cancer cases and 1,159 population controls in Italy, reported that lowered risk of cancer was related to consumption of spices, olive oil, and garlic. You et al. (3), in interviews with 564 patients with gastric cancer and 1,131 controls in China, reported that gastric cancer rates were high and revealed a significant reduction in gastric cancer risk associated with increased consumption of allium vegetables. Steinmetz et al. (4) reported that garlic consumption was inversely associated with colon cancer risk from a prospective cohort study of 41,837 women in Iowa. In a critical review of the epidemiological literature, Fleischauer et al. (5) reported that evidence from available studies nevertheless suggests that garlic consumption has a preventive effect on stomach and colorectal cancers.
AGE is a processed garlic product. It is extracted in a long-term process, standardized with S-allylcysteine (SAC)4 (6), and listed in the U.S. Pharmacopoeia/NF as Garlic Fluidextract in a monograph (7). AGE has been widely studied in various pharmacological and biological areas, including cancer, cardiovascular, immunological, metabolism, and other categories. Due to the nature of the aqueous ethanol extraction process, AGE's main constituents are water-soluble compounds. During what is called the aging process of extraction, many volatile and unstable chemical compounds such as allicin—a thiosulfinate—are converted to more stable compounds and used to create unique compounds, such as S-allylmercaptocysteine (SAMC) and others. Because AGE lacks harsh or toxic compounds, it can be taken by humans for a long time without toxic side effects or contraindications with medications (8–11). Among the effects of AGE, it has been reported to exhibit antitumor activities. The related mechanisms of AGE and its organosulfur constituents were reported in several animal studies. For example, AGE inhibited skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mice and had antitumor-promoting activity (12). SAC, one of the organosulfur constituents of AGE, inhibited 1,2-dimethylhydrazine (DMH)-induced colonic tumorigenesis and nuclear aberrations in a dose-dependent manner and stimulated hepatic and colonic glutathione S-transferase (GST) activity, which is known to assist in detoxifying many carcinogens, including carcinogens in the liver and colon (13); AGE also reduced the incidence of mammary tumors in rats induced by DMBA, and the incidence was proportionally correlated with reduction of DMBA-bound DNA (14). Furthermore, AGE inhibited the growth of Sarcoma-180 and Lewis lung cancer cell line (LL/2) lung carcinoma cells transplanted into mice, and increased natural killer (NK) and killer activities of spleen cells (15). Thus, these and other reports suggest that AGE may have cancer-preventive effects.
Endoscopy is widely used for diagnosis and treatment of colorectal cancer and adenomas. Colonoscopy has been used in several clinical intervention studies to investigate the preventive efficacy of dietary ingredients and drugs, such as dietary fiber (16,17), calcium (18), antioxidant vitamins (19), aspirin (20), and whether slindac (21) or celecoxib (22) in familial adenomatous polyposis may be able to prevent or treat colorectal adenomas.
We conducted a preliminary double-blind clinical intervention trial to evaluate the effect of AGE on the development of colorectal adenomas in patients using an established colonoscopy method (23).
Epidemiological aspect and background of AGE in Cancer. Case-control epidemiological studies in northeast China (3) and Italy (2) showed strong inverse trends in the development of stomach cancer risk with an increase in dietary intake of garlic. Furthermore, a number of animal studies have reported inhibitory effects of garlic and its constituents on the development and growth of cancer. Specifically, AGE and its constituents have demonstrated anticancer effects in an array of cancer models, including bladder tumors, melanoma cells, neuroblastoma cells, skin cancer, breast cancer, colon cancer, prostate cancer, esophageal cancer, stomach and lung cancer, prostate cancer, and erythroleukemia and aflatoxin-induced mutagenesis, as seen in the studies as listed in Table 1.
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Inhibition of growth of carcinogen-induced tumors of the colon: aberrant crypt foci data and other studies. Wargovich (25) found that diallyl sulfide (DAS), a constituent of garlic, significantly reduced (by 74%) the incidence of colon cancer induced by 20 weekly injections of the carcinogen DMH. Also, DAS and SAC, a constituent of AGE, significantly reduced the incidence of colon cancer induced by a carcinogen, DMH. The two compounds, as well as various other organosulfur compounds in AGE, stimulated GST activity (13) and also significantly inhibited nuclear damage caused by DMH, thus decreasing the toxicity of this carcinogen (26).
Aberrant crypt foci are regarded as the most likely precursors of colon cancer. SAC administration inhibited development in the colon of one-third to one-half of the foci induced by DMH when given prior to the carcinogen (initiation phase). Furthermore, SAC was found to enhance GST activity significantly not only in the liver, but also in the proximal and middle small bowel. Thus, SAC inhibited the development of precancerous lesions in the colon and enhanced the activity of enzyme systems in the liver and small intestine that detoxify carcinogens (27). The administration of 0.4 and 0.8 maximum-tolerated doses of SAC incorporated into the experimental diet significantly decreased the number of aberrant crypt foci when given during initiation, but had no effect during promotion induced by the carcinogens DMH or azoxymethane (AOM). Rats given S-ethylmercaptocysteine, S-propylmercaptocysteine, and S-propaglylcysteine exhibited increased foci, but this was determined to be due to decreased food intake caused by the compounds (28).
Additional research by Wargovich's group found that AGE could change the metabolism of the carcinogen AOM and thus inhibit formation of AOM-induced aberrant crypt foci (29). Rats (F344 male) were given AOM (15 mg/kg weekly, intraperitoneally) for 2 wk. In the initiation study, they were also given AGE (120, 600, or 3000 mg/kg) for three consecutive days 1 wk prior to and including the 2-wk period of exposure to AOM. AGE significantly inhibited AOM-induced aberrant crypt foci. When AGE was administered 2 wk after AOM treatment for 4 wk (postinitiation), it had only a mildly preventive effect (29).
Intervention human clinical trial: effect of AGE on colorectal adenomas. Patients enrolled in this clinical study were between 40 and 79 y old, who were determined by colonoscopy to be carrying colorectal adenomas and whose adenomas were removed by polypectomy if their sizes were >5 mm in diameter. This trial was approved by the Institutional Review Board (IRB) at the Hiroshima University Hospital, and all subjects provided written informed consent.
Two dosage preparations of AGE were supplied by Wakunaga Pharmaceutical Co., Ltd. An active, high-dose form consisted of six capsules of high AGE, containing the equivalent of 2.4 mL of AGE daily. The control, low-dose form consisted of six capsules, containing the equivalent of 0.16 mL of AGE daily.
Due to IRB approval and ethical reasons, in addition to the blinded manner, a low concentration of AGE was needed to function as the control preparation because patients in both groups carried colon cancer. Each eligible subject was randomly assigned to each test preparation in order of enrollment and took it at a dose of three capsules twice a day for 12 mo. A research assistant broke the blind control after data and evaluated subjects were fixed.
Follow-up large bowel endoscopy was performed at 6 and 12 mo after intake of either preparation and the endoscopists recorded the location and size of any and all colorectal adenomas. When an adenoma was removed by polypectomy, its sample was examined histologically using the standard technique.
Among 51 enrolled patients (25 in the active group, 26 in the control group), 37 patients (19 in the active group, 18 in the control group) completed the study. Twelve patients were withdrawn within 6 mo—one for pretreatment of poor follow-up colonoscopies, one who regularly took an aspirin preparation prohibited in the test protocol, and the rest who had personal or family issues. The administered baseline characteristics of the subjects who completed the study are shown in Table 2, and there was no significant difference in two groups.
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Possible mechanisms of action. Many in vitro and in vivo studies have suggested possible cancer-preventive effects of AGE and its constituents. In 1990, the U.S. National Cancer Institute initiated the Designer Food Program to determine which foods played an important role in cancer prevention and concluded that garlic may be the most potent food in terms of cancer-preventive properties (1). The mechanisms of anticancer effects of garlic and its constituents have been examined using several chemical carcinogens and mutagens both in vivo and in vitro. Organosulfur compounds of garlic have been shown to inhibit growth of tumor models and to modulate the activity of diverse chemical carcinogens.
Enhancement of detoxifying enzymes Anticancer mechanisms include detoxification of carcinogens or carcinogenic metabolites and inhibition of the formation of carcinogenic metabolites. Constituents in AGE, such as SAC, caused a significant increase in GST activity, which is responsible for detoxification of a variety of electrophilic xenobiotics, including benzo(a)pyrene [B(a)P] metabolites of mouse stomach (30). This activity increase occurred as a result of increased de novo synthesis of the enzyme protein.
The incidence and frequency of colon tumors induced in female CF-1 mice were significantly inhibited by SAC pretreatment. SAC enhanced GST activity in the liver and increased isozymes of GST, GST-
, and GST-µ. These results suggested that SAC exhibited chemopreventive activity by exerting specific effects on carcinogen detoxification systems. AGE reduced the excretion of the chlorzoxazone (CZX) metabolite, 6-OH-hydroxychlorzoxazone (6-OHCZX) (31).
AGE and S-methyl cysteine (SMC) inhibited the area of glutathione S-transferase placental form (GST-P)-positive foci, which are the most effective markers for diethylnitrosamine initiated hepatocellular lesions. SMC decreased the number of GST-P-positive foci when given in both the initiation and promotion stages. SMC inhibited ornithine decarboxylase activity and decreased the proportion of hepatocytes expressing proliferating cell nuclear antigen. Moreover, SMC induced the early response proto-oncogenes, c-jun mRNA transcriptions, through down-regulation.
Inhibition of both the formation and bioactivation of carcinogenic nitrosamines SAC inhibits the formation and bioactivation of the liver carcinogen, nitrosomorpholine (NMOR). Adding SAC to a solution of sodium nitrite and morpholine prevented these two compounds from generating NMOR. SAC also prevented NMOR's ability to mutate a cell model (31). Further, it was found that SAC, DAS, and diallyl disulfide (DADS) were more effective than isomolar ascorbic acid in reducing NMOR mutagenicity (32).
The tumor cytotoxicity of most classic antitumor drugs is thought to be mediated by their ability to induce apotosis. SAMC, a unique compound generated during the garlic aging process and found only in AGE, inhibited growth of two erythroleukemia cell lines, HEL and OCIM-1 (33), in a dose-dependent manner. Radiolabeled thymidine incorporation was reduced in cells treated with SAMC, and analysis of high-molecular-weight DNA showed fragmentation. SAMC appears to be an effective antiproliferative agent against erythroleukemia cells that induces cell death by apoptosis. SAMC also reduced secretion and activity of prostate-specific antigen and prostate-specific membrane antigen in androgen-responsive human prostate carcinoma cells (LNCaP) (34). Furthermore, SAMC diminished cell growth and altered polyamine concentrations. The results suggest that SAMC may impede the polyamine-synthesizing enzyme, ornithine decarboxylase, either by enhancing the formation of reduced glutathione, a known inhibitor of ornithine decarboxylase, or by reacting directly with ornithine decarboxylase at its nucleophilic thiol moiety.
Inhibition of carcinogen binding to DNA The binding of carcinogens to DNA is one mechanism in initiation of carcinogenesis. There are several experimental procedures concerning the preventive effects of garlic on formation of DNA adducts. Liu et al. (14) determined the influence of garlic powder dietary supplements on DMBA-induced mammary tumors and on the in vivo occurrence of mammary DMBA-DNA adducts in rats. Consumption of garlic powder significantly depressed the in vivo binding of DMBA to mammary cell DNA. GST in mammary tissue from rats fed dietary garlic powder increased. The provision of dietary raw garlic powder or its water extract reduced DMBA-DNA binding. Although raw garlic powder did not significantly influence the occurrence of DMBA-DNA adducts, AGE reduced formation of DMBA adducts in mammary tissue. SAC also decreased binding of DMBA to DNA (24). Hageman et al. (35) observed that SAC significantly decreased B(a)P-DNA adduct formation in stimulated human peripheral blood lymphocytes in vitro. AGE enhanced selenite's inhibition of DMBA-induced mammary epithelial cell DNA adducts. Combining selenite with AGE or SAC further inhibited formation of DNA adducts (36).
Indirect antitumor effects via immune enhancement Another possible mechanism of cancer prevention and suppression of cancer progression is immune enhancement by garlic, especially AGE. Garlic is a possible biological response modifier. Weisberger et al. (37) first reported the augmentation of tumor immunity by garlic and subsequently a variety of immunostimulatory effects of garlic have been reported. Because certain diseases can be caused by immune dysfunction, modification of immune functions by garlic may contribute to the treatment and prevention of these diseases.
There is also evidence that garlic may modulate antitumor immunity. The aqueous extract and the polar fraction increased interleukin (IL)-1 production, and the thiosulfinate fraction enhanced NK activity. Aqueous garlic extract increased IL-2 production, but did not stimulate lymphocyte blastogenesis.
Kyo et al. (15) found that AGE could be a significant immunopotentiator and could exhibit antitumor activity through immune modulation. AGE inhibited the growth of Sarcoma-180 by 50% and LL/2 by 20%. Killer cell activity of the spleen against Sarcoma-180 was significantly enhanced by AGE (P < 0.01) but not by polysaccharide of kawaratake (PSK), a positive control drug, and NK cell activity against the YAC-1 cell line was enhanced by both AGE (P < 0.01) and PSK (P < 0.05). Because AGE had no direct effect on LL/2 and Sarcoma-180 in vitro, this suggests that its effects were via immune enhancement and not cytotoxicity (15,38).
AGE was found to have some ability to directly kill MBT2 bladder-tumor cells in test tubes (39). It also significantly suppressed tumor development in mice implanted with bladder cancer cells, reducing tumor incidence and growth by 40% and 60%, respectively, without apparent toxicity or side effects (40). Its effects were similar to that of Bacillus Calmette-Guérin. It was suggested the AGE may be an excellent adjuvant to traditional treatment (39,40).
AGE, and its protein fraction 4 (F4), enhanced the cytotoxicity of human peripheral blood lymphocytes against tumor cells. Lau et al. (41) determined the effects of AGE and F4 on the chemiluminescent oxidative burst of the murine J774 macrophage cell line and thioglycollate-elicited peritoneal macrophages obtained from BALB/c mice. Significant dose-related augmentation of the oxidative burst was observed with AGE and the protein fraction. The protein fraction also enhanced T-lymphocyte blastogenesis. The data suggest that garlic compounds may serve as biological response modifiers by augmenting macrophage and T-lymphocyte functions. Hirao et al. (42) observed that F4 strongly stimulates mice peritoneal macrophages in terms of glucose utilization and exhibits cytostatic activity in vitro. F4 also has a mitogenic activity on spleen cells. In vivo, F4 induced the stimulation of carbon clearance activity in mice. Moreover, this protein fraction significantly stimulated the lymphokine (IL-2)-activated killer activity. The protein fraction also enhanced the proliferation of lymphocytes induced by IL-2 and concanavalin-A, suggesting a possible reduction of the dosage of IL-2 in cancer immunotherapy (43).
These results indicate that F4 is a very efficient immunopotentiator and may be used for immunotherapy. AGE stimulated the proliferation of mouse spleen cells and the release of cytokines, such as IL-2, tumor necrosis factor- and interferon-
, increased NK activities, and enhanced phagocytosis of peritoneal macrophages.
Such immune stimulations may be one of the possible mechanisms of the anticancer effect of AGE and its constituents.
Antimutagenic effect Naturally occurring substances of plant origin are known to possess antimutagenic potential. Several antitumor effects through antimutagenic mechanisms were reported. Dion et al. (44) found that AGE significantly reduced the in vitro formation of NMOR. SAC and its nonallyl analog S-propyl cysteine effectively blocked NMOR formation. SAC reduced the mutagenicity of NMOR in Salmonella typhimurium TA100. SAC reduced the number of histidine revertants per plate, whereas DADS reduced mutant colony number. Six organosulfur compounds, DADS, dipropyl disulfide, DAS, allyl methyl sulfide, allyl mercaptan, and cysteine inhibit the mutagenicity of boiled pork juice using S. typhimurium TA98 in the presence of the rat liver microsomal fraction (S-9) (45). These results suggest that garlic compounds tested in this study are antimutagenic and, potentially, anticarcinogenic.
Using S. typhimurium TA100 as the bacterial tester strain and S-9 as the metabolic activation system, Yamasaki et al. (46) showed that allixin, which was identified as a stress compound produced by garlic and one of the constituents in AGE, inhibited back mutation induced by aflatoxin B1 (AFB1). Allixin inhibited [3H]-AFB1 binding to calf thymus DNA and reduced formation of AFB1-DNA adducts. In addition, allixin exhibited a concentration-dependent inhibition of the formation of organosoluble metabolites and the glutathione conjugates of [3H]-AFB1. Allixin inhibited AFB1-induced mutagenesis and binding of metabolites to DNA. Nishino et al. (47) proved the antitumor-promoting activity of allixin. Allixin inhibited the enhanced phospholipid metabolism of cultured cells induced by a tumor promoter, TPA. Furthermore, allixin suppressed the promoting activity of TPA on skin tumor formation in DMBA-initiated mice. Das et al. (48) observed that garlic extract significantly reduced clastogenicity of three mutagens, mitomycin C, cyclophosphamide, and sodium arsenate.
Conclusions. The results of this trial, and of previous epidemiological and basic studies that are supportive and consistent with this trial, suggest that AGE has a suppressive effect on progression of colorectal adenomas in humans. This effect seems to be multifactorial and reduces many risk factors of cancer. It is urgently necessary to perform larger scale investigations to confirm this trial and its positive effects.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author Disclosure: Harunobu Amagase is employed by Wakunaga of America, Ltd.
4 Abbreviations used: AFB1, aflatoxin B1; AOM, azoxymethane; B(a)P, benzo(a)pyrene; CZX, chlorzoxazone; DAS, diallyl sulfide; DADS, diallyl disulfide; DMBA, 7,12-dimethylbenz[a]anthracene; DMH, 1,2-dimethylhydrazine; GST, glutathione S-transferase; GST-P, glutathione S-transferase placental form; 6-OHCZX, 6-OH-hydroxychlorzoxazone; IL, interleukin; LL/2, Lewis lung carcinoma cells; NK, natural killer; NMOR, nitrosomorpholine; PSK, polysaccharide of kawaratake; membrane; SAC, S-allyl cysteine; SAMC, S-allylmercaptocysteine; SMC, S-methyl cysteine; TPA, 12-O-tetradecanoylphorbol-13-acetate.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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