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Δρ. ΔΗΜΗΤΡΙΟΣ ΝΙΚΟΛΑΟΥ ΓΚΕΛΗΣ

Ωτορινολαρυγγολόγος
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Email: pharmage@otenet.gr


Antioxidant, anticancer action and therapeutic efficacy of Allium sativum [garlic]©

alt

Dr Dimitrios N. Gelis, MD, DDS, PhD, ORL, Korinthos, Greece

www.gelis.gr, 

www.pharmagel.gr, 

www.gkelanto.gr, 

www.orlpedia.gr, 

www.aqllergopedia.gr

alt

Geli Aikaterini, MD, Radiologist, with special imterest in Medical Nutrition, Environmental Medicine

Complementary and alternative medicines are gaining popularity among general population because of their safety profile and easy administration. Garlic, in particular, is considered to be one of the best disease-preventive foods because of its potent and widespread effects [1]

 

Garlic has been shown to exert its beneficial effects against a wide spectrum of diseases, including cancer, diabetes, and microbial infections, as well as immunological and cardiovascular disorders [2].

 

Allium sativum (L.) is rich in antioxidants which help destroy free radicals particles that can damage cell membranes and DNA, and may contribute to the aging process as well as the development of a number of conditions, including heart disease and cancer.

Antioxidants neutralize free radicals and may reduce or even help prevent some of the damage they cause over time.

Preclinical studies have shown that fresh garlic extracts, aged garlic, garlic oil and specific organosulfur compounds generated by processing garlic could alter carcinogen metabolism, inhibit tumor cell growth [3]. 

 

The antioxidant activity of fresh Allium sativum L. (garlic) is well known and is mainly due to unstable and irritating organosulphur compounds. Fresh garlic extracted over a prolonged period (up to 20 months) produces odourless aged garlic extract (AGE) containing stable and water soluble organosulphur compounds that prevent oxidative damage by scavenging free radicals [4].

Considerable evidence in recent years suggests that garlic has anti-proliferative effects against various types of cancer. 

Allicin is a major component of crushed garlic. Although it is sensitive to heat and light and easily metabolized into various compounds such as diallyl disulfide, diallyl trisulfide, and diallyl sulfide, allicin is still a major bioactive compound of crushed garlic . Allicin of garlic shows great potential as a novel chemopreventive agent for the prevention of liver cancer [5].

 

Garlic contains water-soluble and oil-soluble sulfur compounds. Oil-soluble compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene  [6].

 

 are more effective than water-soluble compounds in protection against cancer. DADS, a major organosulfur compound derived from garlic, can decrease carcinogen-induced cancers in experimental animals and inhibit the proliferation of various types of cancer cells. Its mechanisms of action include: the activation of metabolizing enzymes that detoxify carcinogens; suppression of the formation of DNA adducts; antioxidant effects; regulation of cell-cycle arrest; induction of apoptosis and differentiation; histone modification; and inhibition of angiogenesis and invasion [7].

Recent studies have suggested that anticarcinogenic effects of certain garlic compounds may implicate at least in part a modulation of histone acetylation, a process involved in the regulation of gene expression, resulting from the inhibition of histone deacetylase activity [8].

 

The ability of Organic sulfur compounds  [OSCs] to hinder cancer cell proliferation and viability tightly correlates with the length of the sulfur chain. Current data support a mechanism of mitotic arrest of cancer cells due to the alteration of the microtubule network, possibly as a consequence of the high reactivity of sulfur atoms against the thiol groups of different cellular macromolecules controlling crucial regulatory functions [9].


Garlic and the prostate cancer 

S-allylcysteine (SAC) was identified as a potent compound derived from garlic. Liu ZLi M, et al [2012] in their study  evaluated the anticancer effects of SAC on androgen-independent human prostate cancer (PC-3) cells and to elucidate the possible mechanisms. PC-3 cells were incubated with SAC at three different concentrations. Cell growth was determined by Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assay. Cell cycle and apoptosis were determined by flow cytometric assay. The expression of apoptosis-related molecules was detected by Western blot analysis. Yhey found that SAC suppressed the proliferation of PC-3 cells and led to cell cycle arrest at the G0/G1 phases, as well as inducing cell apoptosis which was accompanied by the decreased expression of Bcl-2 and increased expression of Bax and caspase 8. This study demonstrated the chemopreventive activity of SAC in vitro, and that SAC may be a promising candidate for prostate cancer treatment [10].

 

Garlic constituent diallyl trisulfide (DATS) inhibits growth of cultured and xenografted human prostate cancer cells in association with apoptosis induction, DATS-induced apoptosis in prostate cancer cells is mediated in part by suppression of XIAP protein expression, and that XIAP represents a viable biomarker of DATS response for future clinical investigations [11].

 

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in prostate carcinogenesis. It has been demonstrated that  diallyl trisulfide (DATS), a promising cancer-chemopreventive constituent of processed garlic, inhibits phosphorylation of STAT3 inprostate cancer cells in culture and in vivo,  but activation of this oncogenic transcription factor is largely dispensable for cellular responses to DATS. Ability of DATS to overcome STAT3 activation is a therapeutic advantage for this chemopreventive agent [12].

 

Garlic and endometrial cancer

Data from an Italian case-control study. found a moderate protective role of allium vegetables on the risk of endometrial cancer [13].

 

Garlic and lung cancer

Lung cancer is the leading cause of cancer-related mortality all over the world. In recent years, pulmonary adenocarcinoma has surpassed squamous cell carcinoma in frequency and is the predominant form of lung cancer in many countries.

Diallyl trisulfide  [DATS] administration prevents progression to invasive carcinoma and lung metastasis in TRAMP mice [14]. Epidemiological investigations have shown an inverse relationship between garlic (Allium sativum) consumption and death rate from many cancers [15].

 

Protective effect of garlic on the development of cancer has been reported in the in vitro and in vivo experimental studies. Raw garlic consumption of 2 times or more per week is inversely associated with lung cancer [16].

 Protective association between intake of raw garlic and lung cancer has been observed with a dose-response pattern, suggesting that garlic may potentially serve as a chemopreventive agent for lung cancer [16].

 

Garlic and skin cancer

Diallyl trisulfide (DATS) is more potent than mono- and disulfides against skin cancer. DATS inhibits cell growth of human melanoma A375 cells and basal cell carcinoma (BCC) cells by increasing the levels of intracellular reactive oxygen species (ROS) and DNA damage and by inducing G2/M arrest, endoplasmic reticulum (ER) stress, and mitochondria-mediated apoptosis, including the caspase-dependent and -independent pathways [17].


Garlic and hematologic malignancies

The use of garlic and grape seed may be associated with reduced risk of hematologic malignancies [18].


Garlic and stomach and colorectal cancer

The chemopreventive effects of Allium vegetables (onions, garlic, shallots, leeks, chives, and so forth) have been studied extensively, In a meta-analysis, consumption of high levels of Allium vegetables reduced the risk for gastric cancer risk. Evidence from available studies nevertheless suggests a preventive effect of garlic consumption in stomach and colorectal cancers.Because of potential confounding factors and exposure misclassification, further studies are required to establish this association [19].


Garlic and breast  cancer

Garlic and garlic-derived compounds reduce the development of mammary cancer in animals and suppress the growth of human breast cancer cells in culture. Oil-soluble compounds derived from garlic, such as diallyl disulfide (DADS), are more effective than water-soluble compounds in suppressing breast cancer.

Mechanisms of action include the activation of metabolizing enzymes that detoxify carcinogens, the suppression of DNA adduct formation, the inhibition of the production of reactive oxygen species, the regulation of cell-cycle arrest and the induction of apoptosis.

Selenium-enriched garlic or organoselenium compounds provide more potent protection against mammary carcinogenesis in rats and greater inhibition of breastcancer cells in culture than natural garlic or the respective organosulfur analogues. DADS synergizes the effect of eicosapentaenoic acid, a breastcancer suppressor, and antagonizes the effect of linoleic acid, a breast cancer enhancer.

Moreover, garlic extract reduces the side effects caused by anti-cancer agents. Thus, garlic and garlic-derived compounds are promising candidates for breast cancer control  [20].


Garlic and Alzheimer's disease (AD)

Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD [21].


Garlic and cardiovascular disorders

Most of the research on garlic has indicated that garlic and its active compounds are effective in reducing cardiovascular and metabolic risk by normalizing abnormal plasma lipids, oxidized low density lipoproteins, abnormal platelet aggregation, high blood pressure, and cardiac injury. Some of the beneficial effects of dietary garlic against cardiovascular disorders are mediated via the generation of hydrogen sulfide and nitric oxide in cardiomyocytes and endothelial cells.

Garlic has the potential to protect the heart against myocardial infarction, doxorubicin-induced cardiotoxicity, arrhythmia, hypertrophy, and ischemia-reperfusion injury. The induction of cardiac endogenous antioxidants and the reduction of lipid peroxidation by garlic has been reported by several different groups.

 Other mechanisms, such as regulating ion channels, modulating Akt signaling pathways, histone deacetylase inhibition, and cytochrome P450 inhibition, could be responsible for the cardioprotective effect of garlic.

Although several mechanisms have been identified for the cardioprotective effect of garlic, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases [22].

 

Various clinical trials and meta-analyses conducted have shown positive impact of garlic in cardiovascular-disease prevention especially its effects on lipid levels; however, some contradictory results are also reported. Similarly, its effects on hypertension control, and platelet are also mild with limited data availability.

The possible reason for these inconsistent results is the difference in preparations with diverse composition, variations in sulphur content present in different garlic preparations used, and methodological variations in subject recruitment, duration of study, dietary control and so forth.

Garlic can be used as an adjuvant with lipid-lowering drugs for control of lipids, however, its role as a main therapeutic agent cannot be recommended and it is suggested that more meta-analyses using standardized preparations with a close watch on methodological shortfalls should be conducted to prove its role [1].

 

Various clinical trials and meta-analyses conducted have shown positive impact of garlic in cardiovascular-disease prevention especially its effects on lipid levels; however, some contradictory results are also reported. Similarly, its effects on hypertension control, and platelet are also mild with limited data availability.

The possible reason for these inconsistent results is the difference in preparations with diverse composition, variations in sulphur content present in different garlic preparations used, and methodological variations in subject recruitment, duration of study, dietary control and so forth[23]. 

Allicin lowered blood pressure and triglyceride levels in spontaneously hypertensive rats. This effect was not mediated through weight loss [24].


Nakasone Y, et al did a   randomized, double-blind, placebo-controlled study which was  designed to determine the effect of a traditional Japanese garlic homogenate-based supplementary diet (GH diet) product on blood pressure (BP) in subjects with prehypertension and in those with mild hypertension. They concludede  that the GH diet was well tolerated, and had a clinically relevant hypotensive effect in adults with mild hypertension, but not in those with prehypertension [25].


Ried K,et al studied  79 general practice patients with uncontrolled systolic hypertension who participated in a double-blind randomised placebo-controlled dose-response trial of 12 weeks received aged garlic extract as an adjunct treatment to existing antihypertensive medication.

This study  suggests aged garlic extract to be an effective and tolerable treatment in uncontrolled hypertension, and may be considered as a safe adjunct treatment to conventional antihypertensive therapy [26].

 

Hypercholesterolemia is associated with an increased risk of heart disease. The effect of garlic on blood lipids has been studied in numerous trials and summarized in meta-analyses, with conflicting results.

This meta-analysis, the most comprehensive to date, includes 39 primary trials of the effect of garlic preparations on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. The findings suggest garlic to be effective in reducing total serum cholesterol by 17±6mg/dL and low-density lipoprotein cholesterol by 9±6mg/dL in individuals with elevated total cholesterol levels (>200mg/dL), provided garlic is used for longer than 2 months.

An 8% reduction in total serum cholesterol is of clinical relevance and is associated with a 38% reduction in risk of coronary events at 50 years of age. High-density lipoprotein cholesterol levels improved only slightly, and triglycerides were not influenced significantly. Garlic preparations were highly tolerable in all trials and were associated with minimal side effects.

They might be considered as an alternative option with a higher safety profile than conventional cholesterol-lowering medications in patients with slightly elevated cholesterol [27].

 

Garlic and Type 2 diabetes mellitus 

Type 2 diabetes mellitus is a chronic disorder characterized by chronic hyperglycemia, with long term macrovascular and microvascular complications. The treatment is lifestyle management, exercise, weight control, and antihyperglycemic drugs such as sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and meglitinide.

Antidiabetic effect of garlic is well documented even in ancient medical literature. Garlicand its active ingredients have been extensively studied for their antidiabetic efficacies in either experimentally induced or genetic animal models ofdiabetes. Human studies are also available where hypoglycemic effect of garlic was reported.

The beneficial effects of garlic are mainly attributed to the presence of volatile sulfur compounds like alliin, allicin, diallyl disulfide, diallyl trisulfide, diallyl sulfide, S-allyl cysteine, ajoene and allyl mercaptan. Garlic and garlic extracts have been shown to be effective in reducing insulin resistance.

herefore, considering the importance of garlic in controlling diabetic complications, several preparations and food processes containing garlic have been patented [29].

Recently, a direct association between high levels of C-reactive protein and serum adenosine deaminase levels in patients with uncontrolled diabetes with long-term complications has been seen. This study was conducted to assess the antihyperglycemic, lipid-lowering, anti-inflammatory, and improving glycemic control of garlic in type 2 diabetes patients with obesity.

Garlic has been shown to have antihyperglycemic and lipid-lowering properties. The additional lowering of C-reactive protein and serum adenosine deaminase levels with garlic suggests that garlic can be a valuable agent in providing good glycemic control and the prevention of long-term complications [28].

Garlic and Osteoarthritis (OA).

Osteoarthritis (OA) is a synovial joint disorder characterised by pain, stiffness, and restricted function. It is often classed as a degenerative disease because the affected joints deteriorate over time [31].

Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action [32].

DAS prevents IL-1beta and MSU crystal induced COX-2 upregulation in synovial cells and chondrocytes and ameliorates crystal induced synovitis potentially through a mechanism involving NF-kappaB. Anti-inflammatory actions of DAS may be of value in treatment of joint inflammation [33].


References

1. Qidwai WAshfaq T. Role of garlic usage in cardiovascular disease prevention: an evidence-based approach. Evid Based Complement Alternat Med. 2013;2013:125649. doi: 10.1155/2013/125649. Epub 2013 Apr 17.

2. Khatua TNAdela RBanerjee SK. Garlic and cardioprotection: insights into the molecular mechanisms. Can J Physiol Pharmacol. 2013 Jun;91(6):448-58. doi: 10.1139/cjpp-2012-0315. Epub 2013 Mar 6.

3. Druesne-Pecollo NLatino-Martel P. Modulation of histone acetylation by garlic sulfur compounds. Anticancer Agents Med Chem. 2011 Mar;11(3):254-9.

4. Capasso A. Antioxidant action and therapeutic efficacy of Allium sativum L. Molecules. 2013 Jan 4;18(1):690-700. doi: 10.3390/molecules18010690.

5. Chu YLHo CTChung JGRajasekaran RSheen LY. Allicin Induces p53-Mediated Autophagy in Hep G2 Human Liver Cancer Cells. J Agric Food Chem. 2012 Aug 15. [Epub ahead of print]

6. Kaschula CHHunter RHassan HTStellenboom NCotton JZhai XQParker MI. Anti-proliferation activity of synthetic ajoene analogues on cancer cell-lines. Anticancer Agents Med Chem. 2011 Mar;11(3):260-6.

7. Yi LSu Q. Molecular mechanisms for the anti-cancer effects of diallyl disulfide. Food Chem Toxicol. 2013 Jul;57:362-70. doi: 10.1016/j.fct.2013.04.001. Epub 2013 Apr 9.

8. Druesne-Pecollo NLatino-Martel P. Modulation of histone acetylation by garlic sulfur compounds. Anticancer Agents Med Chem. 2011 Mar;11(3):254-9.

9. Cerella CDicato MJacob CDiederich M. Chemical properties and mechanisms determining the anti-cancer action of garlic-derived organic sulfur compounds. Anticancer Agents Med Chem. 2011 Mar;11(3):267-71.

10. Liu ZLi MChen KYang JChen RWang TLiu JYang WYe Z. S-allylcysteine induces cell cycle arrest and apoptosis in androgen-independent human prostate cancer cells. Mol Med Rep. 2012 Feb;5(2):439-43. doi: 10.3892/mmr.2011.658. Epub 2011 Nov 2.

11. Kim SHBommareddy ASingh SV. Garlic constituent diallyl trisulfide suppresses x-linked inhibitor of apoptosis protein in prostate cancer cells in culture and in vivo. Cancer Prev Res (Phila). 2011 Jun;4(6):897-906. doi: 10.1158/1940-6207.CAPR-10-0323. Epub 2011 Mar 16.

12. Chandra-Kuntal KSingh SV. Diallyl trisulfide inhibits activation of signal transducer and activator of transcription 3 in prostate cancer cells in culture and in vivo. Cancer Prev Res (Phila). 2010 Nov;3(11):1473-83. doi: 10.1158/1940-6207.CAPR-10-0123. Epub 2010 Oct 19.

13. Galeone CPelucchi CDal Maso LNegri EMontella MZucchetto ATalamini RLa Vecchia C. Allium vegetables intake and endometrial cancer risk. Public Health Nutr. 2009 Sep;12(9):1576-9. doi: 10.1017/S1368980008003820. Epub 2008 Nov 6.

14. Singh SVPowolny AAStan SDXiao DArlotti JAWarin RHahm ERMarynowski SWBommareddy APotter DMDhir R. Garlic constituent diallyl trisulfide prevents development of poorly differentiated prostate cancer and pulmonary metastasis multiplicity in TRAMP mice. Cancer Res. 2008 Nov 15;68(22):9503-11. doi: 10.1158/0008-5472.CAN-08-1677.

15. Li WTian HLi LLi SYue WChen ZQi LHu WZhu YHao BGao CSi LGao F. Diallyl trisulfide induces apoptosis and inhibits proliferation of A549 cells in vitro and in vivo. . Acta Biochim Biophys Sin (Shanghai). 2012 Jul;44(7):577-83. doi: 10.1093/abbs/gms033. Epub 2012 May 17.

 

16. Jin ZYWu MHan RQZhang XFWang XSLiu AMZhou JYLu QYZhang ZFZhao JK. Raw garlic consumption as a protective factor for lung cancer, a population-based case-control study in a chinese population. Cancer Prev Res (Phila). 2013 Jul;6(7):711-8. doi: 10.1158/1940-6207.CAPR-13-0015. Epub 2013 May 8.

17. Wang HCPao JLin SYSheen LY. Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression. Ann N Y Acad Sci. 2012 Oct;1271:44-52. doi: 10.1111/j.1749-6632.2012.06743.x.

18. Walter RBBrasky TMMilano FWhite E. Vitamin, mineral, and specialty supplements and risk of hematologic malignancies in the prospective VITamins And Lifestyle (VITAL) study. Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2298-308. doi: 10.1158/1055-9965.EPI-11-0494. Epub 2011 Jul 29.

19. Zhou YZhuang WHu WLiu GJWu TXWu XT. Consumption of large amounts of Allium vegetables reduces risk for gastric cancer in a meta-analysis. Gastroenterology. 2011 Jul;141(1):80-9. doi: 10.1053/j.gastro.2011.03.057. Epub 2011 Apr 5.

20. Tsubura ALai YCKuwata MUehara NYoshizawa K. Anticancer effects of garlic and garlic-derived compounds for breast cancer control. Anticancer Agents Med Chem. 2011 Mar;11(3):249-53.

21. Ray BChauhan NBLahiri DK. The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD). Curr Med Chem. 2011;18(22):3306-13..

22. Khatua TNAdela RBanerjee SK. Garlic and cardioprotection: insights into the molecular mechanismsCan J Physiol Pharmacol. 2013 Jun;91(6):448-58. doi: 10.1139/cjpp-2012-0315. Epub 2013 Mar 6.

23. Qidwai WAshfaq T. Role of garlic usage in cardiovascular disease prevention: an evidence-based approach. Evid Based Complement Alternat Med. 2013;2013:125649. doi: 10.1155/2013/125649. Epub 2013 Apr 17.

24. Elkayam APeleg EGrossman EShabtay ZSharabi Y. Effects of allicin on cardiovascular risk factors in spontaneously hypertensive rats. . Isr Med Assoc J. 2013 Mar;15(3):170-3.

25. Nakasone YNakamura YYamamoto TYamaguchi H. Effect of a traditional Japanese garlic preparation on blood pressure in prehypertensive and mildly hypertensive adults. Exp Ther Med. 2013 Feb;5(2):399-405. Epub 2012 Nov 20.

26. Ried KFrank ORStocks NP. Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr. 2013 Jan;67(1):64-70. doi: 10.1038/ejcn.2012.178. Epub 2012 Nov 21.

27. Ried KToben CFakler P. Effect of garlic on serum lipids: an updated meta-analysis. Nutr Rev. 2013 May;71(5):282-99. doi: 10.1111/nure.12012. Epub 2013 Mar 7.

28. Kumar RChhatwal SArora SSharma SSingh JSingh NBhandari VKhurana A.

Recent Pat Food Nutr Agric. 2013 Aug 1;5(2):105-27. Antihyperglycemic, antihyperlipidemic, anti-inflammatory and adenosine deaminase- lowering effects of garlic in patients with type 2 diabetes mellitus with obesity. Diabetes Metab Syndr Obes. 2013;6:49-56. doi: 10.2147/DMSO.S38888. Epub 2013 Jan 19.

29. Padiya RBanerjee SK. Garlic as an Anti-diabetic Agent: Recent Progress and Patent Reviews. Recent Pat Food Nutr Agric. 2013 Aug 1;5(2):105-27.

30. Fleischauer ATArab L. Garlic and cancer: a critical review of the epidemiologic literature.J Nutr. 2001 Mar;131(3s):1032S-40S.

 31.Swift A. Osteoarthritis 1: Physiology, risk factors and causes of pain. Nurs Times. 2012 Feb 14-20;108(7):12-5.

32. Williams FMSkinner JSpector TDCassidy AClark IMDavidson RMMacGregor AJ. Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action. BMC Musculoskelet Disord. 2010 Dec 8;11:280. doi: 10.1186/1471-2474-11-280.

33. Lee HSLee CHTsai HCSalter DM. Inhibition of cyclooxygenase 2 expression by diallyl sulfide on joint inflammation induced by urate crystal and IL-1beta. Osteoarthritis Cartilage. 2009 Jan;17(1):91-9. doi: 10.1016/j.joca.2008.05.010. Epub 2008 Jun 24.

 

Last Updated (Thursday, 05 September 2013 21:13)

 
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