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Nutrition and Cancer Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence a
b
b
Valentina Guercio , Carlotta Galeone , Federica Turati & Carlo La Vecchia a
bc
Department of Surgery, University of Siena, Siena, Italy
b
Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy c
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Published online: 12 May 2014.
To cite this article: Valentina Guercio, Carlotta Galeone, Federica Turati & Carlo La Vecchia (2014) Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence, Nutrition and Cancer, 66:5, 757-773, DOI: 10.1080/01635581.2014.904911 To link to this article: http://dx.doi.org/10.1080/01635581.2014.904911
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Nutrition and Cancer, 66(5), 757–773 C 2014, Taylor & Francis Group, LLC Copyright ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.904911
Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence Valentina Guercio Department of Surgery, University of Siena, Siena, Italy
Carlotta Galeone and Federica Turati Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Downloaded by [University of Central Florida] at 23:20 23 August 2014
Carlo La Vecchia Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
There are suggestions of an anticancerogenic effect of allium vegetables and their associated organosulfur components against several cancer types, including gastric cancer, but the issue remains open to discussion and quantification. The present critical review discussed the history, the health properties, the chemistry, the anticancerogenic evidences from experimental studies, and the anticancer mechanisms of allium vegetables. We also summarized findings from epidemiological studies concerning the association between different types of allium vegetables and gastric cancer risk, published up to date. Available data, derived mainly from case-control studies, suggested a favorable role of high intakes of allium vegetables, mainly garlic and onion, in the etiology of gastric cancer. In particular, of 10 studies, 7 suggested a favorable role of high intake of total allium vegetables and gastric cancer. All 14 studies on garlic and most studies on onion (more than 80%) reported a beneficial role of these allium types against gastric cancer. However several limitations, including possible publication bias and the difficulty to establish a dose-risk relationship, suggest caution in the interpretation. Evidences on other types of allium vegetables, as well as on the influence of different gastric cancer anatomical and histological types, are less consistent.
INTRODUCTION Despite substantial declines in incidence and mortality rates over the last half century (1), gastric cancer remains the fourth most common cancer and the second leading cause of cancerrelated deaths in the world (2). About 1 million new gastric cancer cases and almost 740,000 deaths were estimated to have
Submitted 8 October 2013; accepted in final form 10 March 2014. Address correspondence to Carlotta Galeone, IRCCS–Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156, Milan, Italy. Phone: +39 0239014656. Fax: +39 0233200231. E-mail: [email protected]
occurred in 2008, accounting for 8% of all cancer cases and 10% of all cancer deaths. Over 70% of new cases and deaths occurs in developing countries (2). Over 90% of gastric malignancies are adenocarcinomas, which are classified according to the site and the histological types of the tumor. The 2 main tumor anatomical sites of gastric adenocarcinoma are cardia (GCA) and noncardia (GNCA). According to the histotype, gastric adenocarcinoma is classified as intestinal type or diffuse type by the Lauren’s classification (3). However, the histological classification of a gastric adenocarcinoma is sometimes complex because a proportion of gastric cancer presents a hybrid type, comprising a mixture of both intestinal and diffuse types. Despite appreciable declines in GNCA, GCAs have been increasing in incidence since the 1970s, especially among males in the Western countries (4). Similarly, a decline in the incidence of the intestinal type tumors accounts for most of the recent decrease in gastric cancer rates worldwide. In contrast, there is no clear pattern in the incidence of diffuse type gastric carcinoma (5). The overall decline of gastric cancer has been attributed to a decreased prevalence of Helicobacter pylori (H. pylori) infection, which is the key determinant of gastric cancer (6). In addition, a more varied diet, richer in vegetables and fruit (7–9), improvement in food preservation, and greater socioeconomic conditions have played a role, together with the decline in smoking in men (10). Among the favorable dietary factors, allium vegetables and their associated organosulfur constituents have been studied extensively, both in experimental and in human studies. For this reason, we decided to review experimental and epidemiologic data on the issue. Allium History and Health Properties The Allium genus includes approximately 500 species, the most widely used of which are onions (Allium cepa), garlic
757
Downloaded by [University of Central Florida] at 23:20 23 August 2014
758
V. GUERCIO ET AL.
(Allium sativum), leeks (Allium porrum), chives (Allium schoenoprasum), and shallots (Allium ascalonicum). The word Allium is derived from the celtic “all.” signifying hot or burning. The species name sativum means planted, cultivated, or sown (11). Garlic and onion are among the oldest cultivated plants and originated in central Asia. For thousands of years garlic and onion have been used as folk food and medicine in many cultures. There are various ancient medical texts from Egypt, Greece, Rome, China, and India each prescribing medical applications for Allium vegetables. The Codex Ebers, an Egyptian medical papyrus dating to about 1550 B.C., lists 22 formulas in which garlic was used. Slaves working on the great Pyramids were fed garlic daily to keep them free from diseases. In Egypt onion was held in such esteem that it was considered a sacred fruit, something deserved only by gods. During the first Olympic games in Greece, athletes ingested garlic as a stimulant. Furthermore, Hippocrates recommended garlic as a laxative and a diuretic, and Aristophanes and Galenal for the treatment of uterine tumors. The Roman naturalist Pliny the Elder, in his Historia naturalis, cited numerous therapeutic uses for both garlic and onion. The Romans believed that onion gave extra strength and energy to soldiers on the battlefield. Also in the modern era, garlic has been studied and used to treat several diseases. It has an antibiotic effect against H. pylori, Shygella, Escherichia coli, Staphylococcus, Streptococcus, Proteus, Pseudomanos, Salmonella, Klebsiella (12), and Vibrio (including V. cholera) (13). Moreover, garlic juice exhibits a broad spectrum of activity against fungi by inhibiting the Aflatoxin of Aspergillus flavus (OC1 and OC10) (14) and many strains of yeast, including some that cause vaginitis (12). It is also effective against gastrointestinal parasites of humans and animals, such as Entamoeba Histolytica, Hymeno Lepsis Nana and Giardia Lamblia (15). In recent years, garlic and onion have also been recommended for their antiinflammatory, antithrombotic, cholesterol lowering, antioxidant effects, in the absence however of a quantification of their effect. In particular, there is a large amount of scientific literature that found high intake of allium vegetables could reduce the risk of cancer at specific sites, including gastric, colorectal, lung, prostate and breast cancer (11,16,17). Chemestry of Allium Vegetables Organosulfur compounds present in allium vegetables are considered responsible for the beneficial effects of these vegetables. Fresh garlic contains water, carbohydrates, proteins, fiber, and fat, as well as essential amino acids, vitamins, minerals, and approximately 33 sulfur compounds. When garlic is cut, chopped, or crushed, the clove’s membrane is disrupted and the enzyme alliinase metabolizes alliin to allicin (18). Allicin (diallyl thiosulfinate) is responsible for garlic’s typical pungent smell. Allicin in not stable and is further metabolized to produce diallyl sulfide (DAS), diallyl disulfide, diallyl trisulfide (DATS), and other compounds such as ajoene.
Onions mainly contain S-propenylcysteine sulfoxide (18), but also other sulfoxides, including S-propylcysteine sulfoxide and S-methylcysteine sulfoxide (19). S-propenylcysteine sulfoxide, positional isomer of alliin, is called lacrimatory precursor, because it is tranformed by alliinase into the lacrimatory factor propanethial S-oxide. The lacrimatory factor is highly reactive and hydrolyzes to propionaldehyde, sulfuric acid, and hydrogen sulfide; it is also the precursor of several sulfur derivatives (19).
ALLIUM VEGETABLES AND GASTRIC CANCER In Vitro Studies Using proteomic means, the responses of protein expression, induced by DATS, a major component of garlic derivatives, were studied in BGC823 cells, a gastric cancer cell line. Almost 50% of DATS-sensitive proteins (19 of 41) in BGC823 were tightly associated with apoptotic pathways. Moreover, the quantitative real-time RT-PCR experiments offered the dynamic data of mRNA expression, indicating the responses of Annexin I and GST-pi expression within a short period after DATS treatment (20). Effects of DATS on the apoptosis of human gastric cancer cell line MGC803 and the change of activated caspase-3 were observed in another study. After incubation with DATS, MGC803 cells showed typical apoptotic morphologic changes, and the apoptosis rate increased significantly. Moreover, pro-caspase-3 was hydrolyzed and activated in DATS-treated MGC803 cells (21). In Vivo Studies Preclinical studies have provided convincing evidence that several natural organosulfur compounds are effective in affording protection against cancer induced in experimental animals by different carcinogens (22–24). DAS inhibits cancer of the forestomach, colon, esophagus, mammary gland, and lung (11). Experiments were also conducted to establish the effects of DAS administration on aristolochic acid (AA)-derived DNA singlestranded regions and DNA adduct formation in the forestomach of such animals. Administration of DAS intragastrically, prior to AA treatment significantly reduced the number of rats with forestomach tumors. The incidence of AA-induced forestomach tumors was 10% after co-administration of DAS and 60% when AA was administered alone (25). Organosulfur compounds from garlic and onions were also studied for their inhibitory effects on benzo[a]pyrene-induced neoplasia of forestomach of female A/J mice when administered prior to carcinogen challenge. All 4 allylic compounds: allyl methyl trisulfide, allyl methyl disulfide, DAT and DAS inhibited benzo[a]pyrene-induced neoplasia of the forestomach. DAT, which contains 2 allyl groups, was more potent than allyl methyl trisulfide, which contains only 1 allyl group. All 4 allylic compounds induced increased glutathione S-transferase (GST) activity in the forestomach (26).
GASTRIC CANCER AND ALLIUM VEGETABLES
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Epidemiological Studies Several epidemiologic investigations have suggested a possible inverse relation between allium intake and gastric cancer risk. One of the first published studies on this issue was a Japanese case-control study by Haenszel and colleagues, performed in the 1960s and enrolling 220 gastric cancer cases (27). They found an odds ratio (OR) of 0.47 [95% confidence interval (CI), 0.26–0.84) for a frequency of onion consumption ≥21 vs. 24.0 Total allium servings/mo M ≤0.9 1.0–3.0 3.1–8.5 ≥8.6 W ≤0.9 1.0–3.0 3.1–8.5 ≥8.6 Total allium g/day ≤2.9 3.0–20.9 ≥21.0
Type of allium Cases/controls vegetables and Design (n) Study period consumption categories
1.00 0.66 (0.41–1.07) 0.56 (0.34–0.92)
1.00 0.90 (0.60–1.30) 0.80 (0.60–1.20) 0.80 (0.50–1.20)
1.00 1.30 (0.90–1.70) 1.10 (0.80–1.50) 0.80 (0.60–1.10)
1.00 0.60 (0.40–0.80) 0.50 (0.40–0.70) 0.40 (0.30–0.60)
1.00 1.00 0.80
Relative risk (95% confidence interval)
TABLE 1 Characteristics of studies of total allium intake and risk of gastric cancer
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Age, gender, residence, urban/rural status, education, body mass index, total energy intake, and total fruit intake
Age, income, education, smoking (males only), and alcohol drinking (males only)
Age, gender, and family income
Age, gender, study area, social class, residence, migration, body mass index, family history of gastric cancer
Adjustments
761
Epplein et al. (30), 2010
HCC
PCC
102/204
210/630
2005–2006
1999–2000
Sweden Cohort 139/82,002 1997–2005 Swedish Mammography Cohort and the Cohort of Swedish Men China Cohort 338/132,311 1996–2007 Shanghai GNCA Women’s Health Study and Shanghai Men’s Health Study
Serbia
Lazarevic et al. (40), 2010
Cohort studies Larsson et al. (41), 2006
China
Xibin et al. (39), 2002
Total allium (onion, leek and garlic) servings/wk 6.7–11.7 >11.7–20.0 >20.0 W ≤2.9 >2.9–5.5 >5.5–10.2 >10.2
Total allium (spring onion and garlic) By quartiles 1 2 3 4 Total allium (onion, garlic, leek) By tertiles 1 2 3 1.00 1.37 0.88 0.73
1.00 0.82 (0.51–1.31) 0.64 (0.39–1.07) 0.92 (0.58–1.46) 1.00 1.13 (0.78–1.64) 0.94 (0.63–1.41) 1.10 (0.74–1.63)
1.00 0.89 (0.57–1.39) 0.90 (0.58–1.41)
1.00 0.25 (0.06–1.07) 0.11 (0.02–0.6)
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(Continued on next page)
Age, education, smoking, and total energy intake
Age, gender, education, smoking, alcohol, total energy intake, processed meat and diabetes
Age, gender, residence, education, meals regularity, tobacco smoking and history of cancer
Age, gender, residence, income, education, and using refrigerator
762 Design
The Cohort Nether- The Netherlands lands Cohort Study
Country 156/4035 GCA 460/4035 GNCA
1992/1998– 2010
Total allium g/day GCA 5 16 25 38 62 GNCA 5 16 25 38 62 Total allium (onion and garlic) g/day M 0–3, W 0–2 M 3–6, W 2–4 M 4–14, W 4–8 M 14–27, W 8–19 M 27–279, W 19–237
1986/1990–2002
1.00 1.03 (0.75–1.41) 0.89 (0.65–1.21) 0.94 (0.71–1.24) 0.97 (0.76–1.25)
1 0.92 (0.50–1.68) 1.35 (0.83–2.19) 0.95 (0.55–1.65) 1.55 (0.94–2.56) 1 1.32 (0.96–1.83) 0.85 (0.62–1.18) 1.25 (0.93–1.68) 0.97 (0.69–1.35)
Relative risk (95% confidence interval)
Age, gender, education, body mass index, smoking, alcohol, physical activity, energy intake and consumption of red and processed meat
Age, gender, smoking, alcohol, red meat intake and fish intake, fruit, and all other vegetables
Adjustments
HCC = hospital case-control; PCC = population case-control; GCA = gastric cardia adenocarcinoma; GNCA = gastric noncardia adenocarcinoma; M = men; W = women.
Gonzales et al. European Cohort 683/477,312 (33), 2012 countries European Prospective Investigation into Cancer and nutrition
Steevens et al. (32), 2011
Study
Type of allium Cases/controls vegetables and (n) Study period consumption categories
TABLE 1 Characteristics of studies of total allium intake and risk of gastric cancer (Continued)
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763
China
China
Korea
Takezaki et al. (46), 2001
Gao et al. (47), 2002
Kim et al. (51), 2002
Venezuela
Munoz et al. (45), 2001
China
Uruguay
PCC
Sweden
Hansson et al. (43), 1993 Gao et al. (44), 1999
De Stefani et al. (38), 2001
PCC
China
You et al. (36), 1989
HCC
PCC
PCC
PCC
HCC
PCC
PCC
Italy
Buiatti et al. (35), 1989
Design
Country
Case-control study
136/136
98/196
187/333
292/485
160/320
153/234
338/669
564/1131
1016/1159
Cases/controls (n)
1997–1998
1999–2000
1995–2000
1991–1997
1997–2000
1995–1997
1989–1992
1984–1986
1985–1987
Study period
Low Medium High
Times/wk 1.5 low high Times/mo
Nutrition and Cancer Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence a
b
b
Valentina Guercio , Carlotta Galeone , Federica Turati & Carlo La Vecchia a
bc
Department of Surgery, University of Siena, Siena, Italy
b
Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy c
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Published online: 12 May 2014.
To cite this article: Valentina Guercio, Carlotta Galeone, Federica Turati & Carlo La Vecchia (2014) Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence, Nutrition and Cancer, 66:5, 757-773, DOI: 10.1080/01635581.2014.904911 To link to this article: http://dx.doi.org/10.1080/01635581.2014.904911
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Nutrition and Cancer, 66(5), 757–773 C 2014, Taylor & Francis Group, LLC Copyright ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635581.2014.904911
Gastric Cancer and Allium Vegetable Intake: A Critical Review of the Experimental and Epidemiologic Evidence Valentina Guercio Department of Surgery, University of Siena, Siena, Italy
Carlotta Galeone and Federica Turati Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Downloaded by [University of Central Florida] at 23:20 23 August 2014
Carlo La Vecchia Department of Epidemiology, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
There are suggestions of an anticancerogenic effect of allium vegetables and their associated organosulfur components against several cancer types, including gastric cancer, but the issue remains open to discussion and quantification. The present critical review discussed the history, the health properties, the chemistry, the anticancerogenic evidences from experimental studies, and the anticancer mechanisms of allium vegetables. We also summarized findings from epidemiological studies concerning the association between different types of allium vegetables and gastric cancer risk, published up to date. Available data, derived mainly from case-control studies, suggested a favorable role of high intakes of allium vegetables, mainly garlic and onion, in the etiology of gastric cancer. In particular, of 10 studies, 7 suggested a favorable role of high intake of total allium vegetables and gastric cancer. All 14 studies on garlic and most studies on onion (more than 80%) reported a beneficial role of these allium types against gastric cancer. However several limitations, including possible publication bias and the difficulty to establish a dose-risk relationship, suggest caution in the interpretation. Evidences on other types of allium vegetables, as well as on the influence of different gastric cancer anatomical and histological types, are less consistent.
INTRODUCTION Despite substantial declines in incidence and mortality rates over the last half century (1), gastric cancer remains the fourth most common cancer and the second leading cause of cancerrelated deaths in the world (2). About 1 million new gastric cancer cases and almost 740,000 deaths were estimated to have
Submitted 8 October 2013; accepted in final form 10 March 2014. Address correspondence to Carlotta Galeone, IRCCS–Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156, Milan, Italy. Phone: +39 0239014656. Fax: +39 0233200231. E-mail: [email protected]
occurred in 2008, accounting for 8% of all cancer cases and 10% of all cancer deaths. Over 70% of new cases and deaths occurs in developing countries (2). Over 90% of gastric malignancies are adenocarcinomas, which are classified according to the site and the histological types of the tumor. The 2 main tumor anatomical sites of gastric adenocarcinoma are cardia (GCA) and noncardia (GNCA). According to the histotype, gastric adenocarcinoma is classified as intestinal type or diffuse type by the Lauren’s classification (3). However, the histological classification of a gastric adenocarcinoma is sometimes complex because a proportion of gastric cancer presents a hybrid type, comprising a mixture of both intestinal and diffuse types. Despite appreciable declines in GNCA, GCAs have been increasing in incidence since the 1970s, especially among males in the Western countries (4). Similarly, a decline in the incidence of the intestinal type tumors accounts for most of the recent decrease in gastric cancer rates worldwide. In contrast, there is no clear pattern in the incidence of diffuse type gastric carcinoma (5). The overall decline of gastric cancer has been attributed to a decreased prevalence of Helicobacter pylori (H. pylori) infection, which is the key determinant of gastric cancer (6). In addition, a more varied diet, richer in vegetables and fruit (7–9), improvement in food preservation, and greater socioeconomic conditions have played a role, together with the decline in smoking in men (10). Among the favorable dietary factors, allium vegetables and their associated organosulfur constituents have been studied extensively, both in experimental and in human studies. For this reason, we decided to review experimental and epidemiologic data on the issue. Allium History and Health Properties The Allium genus includes approximately 500 species, the most widely used of which are onions (Allium cepa), garlic
757
Downloaded by [University of Central Florida] at 23:20 23 August 2014
758
V. GUERCIO ET AL.
(Allium sativum), leeks (Allium porrum), chives (Allium schoenoprasum), and shallots (Allium ascalonicum). The word Allium is derived from the celtic “all.” signifying hot or burning. The species name sativum means planted, cultivated, or sown (11). Garlic and onion are among the oldest cultivated plants and originated in central Asia. For thousands of years garlic and onion have been used as folk food and medicine in many cultures. There are various ancient medical texts from Egypt, Greece, Rome, China, and India each prescribing medical applications for Allium vegetables. The Codex Ebers, an Egyptian medical papyrus dating to about 1550 B.C., lists 22 formulas in which garlic was used. Slaves working on the great Pyramids were fed garlic daily to keep them free from diseases. In Egypt onion was held in such esteem that it was considered a sacred fruit, something deserved only by gods. During the first Olympic games in Greece, athletes ingested garlic as a stimulant. Furthermore, Hippocrates recommended garlic as a laxative and a diuretic, and Aristophanes and Galenal for the treatment of uterine tumors. The Roman naturalist Pliny the Elder, in his Historia naturalis, cited numerous therapeutic uses for both garlic and onion. The Romans believed that onion gave extra strength and energy to soldiers on the battlefield. Also in the modern era, garlic has been studied and used to treat several diseases. It has an antibiotic effect against H. pylori, Shygella, Escherichia coli, Staphylococcus, Streptococcus, Proteus, Pseudomanos, Salmonella, Klebsiella (12), and Vibrio (including V. cholera) (13). Moreover, garlic juice exhibits a broad spectrum of activity against fungi by inhibiting the Aflatoxin of Aspergillus flavus (OC1 and OC10) (14) and many strains of yeast, including some that cause vaginitis (12). It is also effective against gastrointestinal parasites of humans and animals, such as Entamoeba Histolytica, Hymeno Lepsis Nana and Giardia Lamblia (15). In recent years, garlic and onion have also been recommended for their antiinflammatory, antithrombotic, cholesterol lowering, antioxidant effects, in the absence however of a quantification of their effect. In particular, there is a large amount of scientific literature that found high intake of allium vegetables could reduce the risk of cancer at specific sites, including gastric, colorectal, lung, prostate and breast cancer (11,16,17). Chemestry of Allium Vegetables Organosulfur compounds present in allium vegetables are considered responsible for the beneficial effects of these vegetables. Fresh garlic contains water, carbohydrates, proteins, fiber, and fat, as well as essential amino acids, vitamins, minerals, and approximately 33 sulfur compounds. When garlic is cut, chopped, or crushed, the clove’s membrane is disrupted and the enzyme alliinase metabolizes alliin to allicin (18). Allicin (diallyl thiosulfinate) is responsible for garlic’s typical pungent smell. Allicin in not stable and is further metabolized to produce diallyl sulfide (DAS), diallyl disulfide, diallyl trisulfide (DATS), and other compounds such as ajoene.
Onions mainly contain S-propenylcysteine sulfoxide (18), but also other sulfoxides, including S-propylcysteine sulfoxide and S-methylcysteine sulfoxide (19). S-propenylcysteine sulfoxide, positional isomer of alliin, is called lacrimatory precursor, because it is tranformed by alliinase into the lacrimatory factor propanethial S-oxide. The lacrimatory factor is highly reactive and hydrolyzes to propionaldehyde, sulfuric acid, and hydrogen sulfide; it is also the precursor of several sulfur derivatives (19).
ALLIUM VEGETABLES AND GASTRIC CANCER In Vitro Studies Using proteomic means, the responses of protein expression, induced by DATS, a major component of garlic derivatives, were studied in BGC823 cells, a gastric cancer cell line. Almost 50% of DATS-sensitive proteins (19 of 41) in BGC823 were tightly associated with apoptotic pathways. Moreover, the quantitative real-time RT-PCR experiments offered the dynamic data of mRNA expression, indicating the responses of Annexin I and GST-pi expression within a short period after DATS treatment (20). Effects of DATS on the apoptosis of human gastric cancer cell line MGC803 and the change of activated caspase-3 were observed in another study. After incubation with DATS, MGC803 cells showed typical apoptotic morphologic changes, and the apoptosis rate increased significantly. Moreover, pro-caspase-3 was hydrolyzed and activated in DATS-treated MGC803 cells (21). In Vivo Studies Preclinical studies have provided convincing evidence that several natural organosulfur compounds are effective in affording protection against cancer induced in experimental animals by different carcinogens (22–24). DAS inhibits cancer of the forestomach, colon, esophagus, mammary gland, and lung (11). Experiments were also conducted to establish the effects of DAS administration on aristolochic acid (AA)-derived DNA singlestranded regions and DNA adduct formation in the forestomach of such animals. Administration of DAS intragastrically, prior to AA treatment significantly reduced the number of rats with forestomach tumors. The incidence of AA-induced forestomach tumors was 10% after co-administration of DAS and 60% when AA was administered alone (25). Organosulfur compounds from garlic and onions were also studied for their inhibitory effects on benzo[a]pyrene-induced neoplasia of forestomach of female A/J mice when administered prior to carcinogen challenge. All 4 allylic compounds: allyl methyl trisulfide, allyl methyl disulfide, DAT and DAS inhibited benzo[a]pyrene-induced neoplasia of the forestomach. DAT, which contains 2 allyl groups, was more potent than allyl methyl trisulfide, which contains only 1 allyl group. All 4 allylic compounds induced increased glutathione S-transferase (GST) activity in the forestomach (26).
GASTRIC CANCER AND ALLIUM VEGETABLES
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Epidemiological Studies Several epidemiologic investigations have suggested a possible inverse relation between allium intake and gastric cancer risk. One of the first published studies on this issue was a Japanese case-control study by Haenszel and colleagues, performed in the 1960s and enrolling 220 gastric cancer cases (27). They found an odds ratio (OR) of 0.47 [95% confidence interval (CI), 0.26–0.84) for a frequency of onion consumption ≥21 vs. 24.0 Total allium servings/mo M ≤0.9 1.0–3.0 3.1–8.5 ≥8.6 W ≤0.9 1.0–3.0 3.1–8.5 ≥8.6 Total allium g/day ≤2.9 3.0–20.9 ≥21.0
Type of allium Cases/controls vegetables and Design (n) Study period consumption categories
1.00 0.66 (0.41–1.07) 0.56 (0.34–0.92)
1.00 0.90 (0.60–1.30) 0.80 (0.60–1.20) 0.80 (0.50–1.20)
1.00 1.30 (0.90–1.70) 1.10 (0.80–1.50) 0.80 (0.60–1.10)
1.00 0.60 (0.40–0.80) 0.50 (0.40–0.70) 0.40 (0.30–0.60)
1.00 1.00 0.80
Relative risk (95% confidence interval)
TABLE 1 Characteristics of studies of total allium intake and risk of gastric cancer
Downloaded by [University of Central Florida] at 23:20 23 August 2014
Age, gender, residence, urban/rural status, education, body mass index, total energy intake, and total fruit intake
Age, income, education, smoking (males only), and alcohol drinking (males only)
Age, gender, and family income
Age, gender, study area, social class, residence, migration, body mass index, family history of gastric cancer
Adjustments
761
Epplein et al. (30), 2010
HCC
PCC
102/204
210/630
2005–2006
1999–2000
Sweden Cohort 139/82,002 1997–2005 Swedish Mammography Cohort and the Cohort of Swedish Men China Cohort 338/132,311 1996–2007 Shanghai GNCA Women’s Health Study and Shanghai Men’s Health Study
Serbia
Lazarevic et al. (40), 2010
Cohort studies Larsson et al. (41), 2006
China
Xibin et al. (39), 2002
Total allium (onion, leek and garlic) servings/wk 6.7–11.7 >11.7–20.0 >20.0 W ≤2.9 >2.9–5.5 >5.5–10.2 >10.2
Total allium (spring onion and garlic) By quartiles 1 2 3 4 Total allium (onion, garlic, leek) By tertiles 1 2 3 1.00 1.37 0.88 0.73
1.00 0.82 (0.51–1.31) 0.64 (0.39–1.07) 0.92 (0.58–1.46) 1.00 1.13 (0.78–1.64) 0.94 (0.63–1.41) 1.10 (0.74–1.63)
1.00 0.89 (0.57–1.39) 0.90 (0.58–1.41)
1.00 0.25 (0.06–1.07) 0.11 (0.02–0.6)
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Age, education, smoking, and total energy intake
Age, gender, education, smoking, alcohol, total energy intake, processed meat and diabetes
Age, gender, residence, education, meals regularity, tobacco smoking and history of cancer
Age, gender, residence, income, education, and using refrigerator
762 Design
The Cohort Nether- The Netherlands lands Cohort Study
Country 156/4035 GCA 460/4035 GNCA
1992/1998– 2010
Total allium g/day GCA 5 16 25 38 62 GNCA 5 16 25 38 62 Total allium (onion and garlic) g/day M 0–3, W 0–2 M 3–6, W 2–4 M 4–14, W 4–8 M 14–27, W 8–19 M 27–279, W 19–237
1986/1990–2002
1.00 1.03 (0.75–1.41) 0.89 (0.65–1.21) 0.94 (0.71–1.24) 0.97 (0.76–1.25)
1 0.92 (0.50–1.68) 1.35 (0.83–2.19) 0.95 (0.55–1.65) 1.55 (0.94–2.56) 1 1.32 (0.96–1.83) 0.85 (0.62–1.18) 1.25 (0.93–1.68) 0.97 (0.69–1.35)
Relative risk (95% confidence interval)
Age, gender, education, body mass index, smoking, alcohol, physical activity, energy intake and consumption of red and processed meat
Age, gender, smoking, alcohol, red meat intake and fish intake, fruit, and all other vegetables
Adjustments
HCC = hospital case-control; PCC = population case-control; GCA = gastric cardia adenocarcinoma; GNCA = gastric noncardia adenocarcinoma; M = men; W = women.
Gonzales et al. European Cohort 683/477,312 (33), 2012 countries European Prospective Investigation into Cancer and nutrition
Steevens et al. (32), 2011
Study
Type of allium Cases/controls vegetables and (n) Study period consumption categories
TABLE 1 Characteristics of studies of total allium intake and risk of gastric cancer (Continued)
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763
China
China
Korea
Takezaki et al. (46), 2001
Gao et al. (47), 2002
Kim et al. (51), 2002
Venezuela
Munoz et al. (45), 2001
China
Uruguay
PCC
Sweden
Hansson et al. (43), 1993 Gao et al. (44), 1999
De Stefani et al. (38), 2001
PCC
China
You et al. (36), 1989
HCC
PCC
PCC
PCC
HCC
PCC
PCC
Italy
Buiatti et al. (35), 1989
Design
Country
Case-control study
136/136
98/196
187/333
292/485
160/320
153/234
338/669
564/1131
1016/1159
Cases/controls (n)
1997–1998
1999–2000
1995–2000
1991–1997
1997–2000
1995–1997
1989–1992
1984–1986
1985–1987
Study period
Low Medium High
Times/wk 1.5 low high Times/mo
