Organosulfur compounds and possible mechanism of garlic in cancer (2024)

1.1. Organsulfur constituents in garlic

Blackwood and Fulder (1987) reported that an average clove of garlic weighs between 3 and 6g and contains an average of 1g of carbohydrates (90% of which is in a starchy form called sinistrin), 0.2g of protein, 0.05g of fiber, 0.01g of fat and vitamins A, B₁, B₂, B₃ and C. The Vitamin B₁ (thiamin) is combined with the allicin and called allithiamine and is easily absorbed into the intestine. Garlic contains about 10 different kinds of natural sugars which make up about a fourth of its substances; they include fructose, glucose, inulin and arabinose. Garlic can reduce blood sugar levels (Sheela et al., 1995; Augusti and Sheela, 1996). Fulder and Blackwood (Blackwood and Fulder, 1987) further say that garlic is richer than any other food in adenosine, a nucleic acid which is a building block of DNA and RNA. The primary anti-platelet constituent found in garlic appears to be adenosine (Makheja and Bailey, 1990). Garlic contains approximately 33 sulfur compounds (aliin, allicin, ajoene, allylpropyl disulfide, diallyl trisulfide, sallylcysteine, vinyldithiines, S-allylmercaptocystein, and others), several enzymes (allinase, peroxidases, myrosinase, and others), 17 amino acids (arginine and others), and minerals (selenium, germanium, tellurium and other trace minerals) (Newall et al., 1996). Biological effects of garlic are attributed to its characteristic organosulfur compounds (Agarwal, 1996; Block, 1992). Allicin (diallyl thiosulphate) chemically known as 2-propene-1-sulfinothioc acid S-2-propenyl ester; thio-2-propene-1-sulfinic acid S-allyl ester (The Merck Index, 1989) and discovered by Cavallito and Bailey (1944) in 1944, responsible for garlic’s typical pungent smell. Allicin does not exist in garlic until it is crushed or cut; injury to the garlic bulb activates the enzyme allinase (Stoll and Seebeck, 1951), which metabolizes alliin to allicin (Block, 1985) (Fig. 1).

Allicin is further metabolized to produce diallyl sulphide (DAS), diallyl disulfide (DADS), diallyl trisulfide, allyl methyl trisulfide, dithiins and ajone (Fig. 2) vinyldithiines.

This breakdown occurs within hours at room temperature and within minutes during cooking (Blania and Spangenberg, 1991). Alliin is non protein amino acid based on cysteine and has four stereoisomers but only one isomer is present in garlic. Dried, powdered garlic contains approximately 1% alliin (S-allyl cysteine sulfoxide). According to two studies of garlic preparations, allicin decreased to non-detectable amounts within 1–6days (Yu and Wu, 1989). Allicin can easily diffuse into the internal volume of vesicles or into the cytoplasm of red blood cells. Lipid bilayers do not constitute a barrier for allicin penetration and its diffusion through the lipid bilayer and it does not cause membrane leakage, fusion or aggregation (Miron et al., 2000) findings raise the possibility that in biological systems allicin can penetrate very rapidly into different compartments of the cells and exert its biological effects. Thus, significance of allicin as a biological effectors’ molecule is due not only to its high reactivity with low and high molecular weigh thiols and its prominent antioxidant activity (Rabinkov et al., 1998), but also to its accessibility resulting from high membrane permeability. Due to its high reactivity, allicin was shown to be completely metabolized in the liver (Egen-Schwind et al., 1992). If allicin could even make it to the blood (to be delivered throughout the body), studies have shown that it changes into other compounds within 5min and in the process may oxidize the blood cells causing them to lose their ability to carry oxygen (Freeman and Kodera, 1995). Allicin also decreases ocular pressure (Agarwal, 1996; Block, 1992; Chu et al., 1993). In addition to this, allicin affects the processing of DNA and RNA synthesis (Feldberg et al., 1988). Table 1 showed the chemical compounds found in the garlic bulb. Generally garlic bulb contains approximately 65% water, 28% carbohydrates (mainly fructans), 2.3% organosulfur compounds, 2% protein (mainly alliin), 1.2% free amino acids (mainly arginine), and 1.5% fiber (Blumenthal et al., 2000).

1.2. Possible mechanism in cancer

Several individual compounds have been isolated from garlic and two major groups of compounds that show active anticancer effects have been identified. One group is the lipid-soluble allyl sulfur compounds such as diallyl disulfide (DADS) and diallyl trisulfide (DATS), and the other one is the water-soluble compounds γ-glutamyl S-allylcysteine group such as S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) Thomson and Ali, 2003. There were several mechanisms have been proposed to explain the cancer-preventive effects of garlic and related organosulfur compounds in other Allium vegetables. These include inhibition of mutagenesis, modulation of enzyme activities, inhibition of DNA adduct formation, free-radical scavenging, and effects on cell proliferation and tumor growth. AGE, as the name suggests, produced by aging garlic. Sliced raw garlic stored in 15–20% ethanol for 20months is refereed to as AGE. The AGE garlic acts on several fronts in blocking prostate cancer growth; inhibiting polyamines needed for cell division, increasing breakdown of testosterone, that is needed for prostate cancer growth and reducing prostate specific antigen (PSA) levels, a prostate cancer marker (Pinto et al., 1997, 2000). Other studies showed that S-allyl mercaptocysteine stops the growth of breast cancer cells, erythroleukemia (Sigounas et al., 1997) and colon cancer cells (Xiao et al., 2003). S-allyl mercaptocysteine prevented colon cancer cell growth by 71%, disrupting cellular microtubules that form the cytoskeleton and the mitotic spindle in cells, thus disrupting cell division. In addition, S-allyl mercaptocysteine induced cell suicide (apoptosis) in the colon cancer cells, by activating apoptosis signalling pathway enzymes, including caspase that ultimately kills the cells (Xiao et al., 2003). Although there is evidence supporting these mechanisms for organosulfur compounds, they are still speculative, and further research is needed to support causality between such properties and the cancer-preventive activity in experimental animals.

1.3. Mutagenesis inhibition

Aqueous and methanolic garlic extracts inhibited the mutagenic activity of aflatoxin B₁ in Salmonella typhimurium (Soni et al., 1997). Aqueous garlic extract also decreased the mutagenicity of 4-nitroquinoline-1-oxide in Escherichia coli (Zhang et al., 1989) and the mutagenicity of γ-radiation, hydrogen peroxide, cumene, and t-butyl hydroperoxides in S. typhimurium (Knasmuller et al., 1989).

1.4. Enzyme activities modulation

Organosulfur compounds have been shown to modulate the activity of glutathione S-transferases (GST), a family of enzymes important in detoxification of carcinogens, and cytochromes P450 (CYP), a family of enzymes that activate many chemical carcinogens in experimental animals. Sparnins et al. (1986) first showed that allylmethyltrisulfide (AMTS) increased the activity of GST in the forestomach, small-bowel mucosa, liver, and lung of mice. Other allyl derivatives also increased GST activity in these tissues (Sparnins et al., 1988). Derivatives with a propyl instead of an allyl group were less active or inactive. The induction of GST paralleled the inhibition of benzo[a]pyrene-induced carcinogenesis in the forestomach, but not in the lung, suggesting that increased carcinogen detoxification is only one of the factors responsible for the cancer-preventive effects of organosulfur compounds. These results were partially confirmed by Sumiyoshi and Wargovich (1990), who found a greater effect of thioallyl than thiopropyl derivatives in inducing hepatic and colonic GST in mice. In contrast, DAS did not increase GST activity in mouse liver (Wargovich, 1987) or in a culture of rat hepatocytes (Hayes et al., 1987). The activity of mammary and liver GST was increased by the addition of garlic powder to the diet of rats. The maximum activity of GST did not coincide with maximum inhibition of carcinogenesis, however, further indicating that increased GST activity does not account fully for the protection provided by garlic powder against carcinogenesis. Thus, the effects on enzymes that activate chemical carcinogens are not sufficient to explain the cancer-preventive activity. For example, an oral dose of DAS suppressed esophageal carcinogenesis induced by N-nitrosomethylbenzylamine in rats and significantly reduced the microsomal conversion of this nitrosamine in liver but not in esophagus (Wargovich et al., 1988). In addition, the prevention of benzo[a] pyrene-induced forestomach cancer in mice by organosulfur compounds is not attributable to a reduction in the activity of CYP1A1 (Srivastava et al., 1997). DADS in the diet increased not only the activity of GST but also that of other detoxifying enzymes, including reduced nicotinamide adenine dinucleotide phosphate [NAD (P)H] – dependent quinone oxidoreductase, which is involved in detoxification of activated quinine metabolites of benzo[a]pyrene, and of uridine diphosphate (UDP) – glucuronosyl transferase in rat tissues (Munday and Munday, 1999). DAS acted as a competitive inhibitor of N-dimethylnitrosamine demethylase activity (Brady et al., 1988). It also decreased the activity of CYP2E1 in a time- and dose-dependent manner and induced the activities of CYP2B1 and pentoxy- and ethoxyresorufin dealkylases in hepatic microsomes (Brady et al., 1991). An increase in CYP2B1 mRNA was also observed. Treatment with the DAS metabolites diallyl sulfoxide (DASO) and diallylsulfone (DASO₂) had similar effects on rat hepatic monooxygenase activities (Brady et al., 1991; Pan et al., 1993). Reicks and Crankshaw (1996) reported that DAS, DADS, and AMS decreased p-nitrophenol hydroxylase activity and CYP2E1 protein concentration in rat liver. When the diet of rats was supplemented with DAS/DADS, DADS increased the activities of several monooxygenases and transferases in intestine and liver; the protein levels of epoxide hydrolase and CYP2B1/2 were also increased. DADS also decreased CYP2E1 level in liver. The effects of DAS were similar to those of DADS in liver, but only epoxide hydrolase activity and CYP2B1/2 protein levels were increased in the intestine. In a study of the effect of garlic oil, DAS, and DADS on the activities of several metabolizing enzymes in the liver of rats fed high-fat diets (Sheen et al., 1999), GST activity was increased by all treatments. Garlic oil induced the expression of the placental form of GST and CYP2B1 and decreased the expression of CYP2E1. DAS and DADS also modulated these enzymes, but DAS increased mainly CYP2B1, whereas DADS increased mainly GST activity; similar effects were observed on CYP2E1 expression. DAS and its oxidation derivatives DASO and DASO₂ are conjugated with glutathione, in rats (Jin and Baillie, 1997). No study has investigated the effects of possible GST polymorphisms in the deactivation of these Allium vegetable-derived compounds, although this could provide some explanations of differential effects in humans. Modulation of the activity of arylamine N-acetyltransferase, a polymorphic enzyme that deactivates arylamines and activates some heterocyclic dietary amines, was addressed in a few studies. The slow and fast acetylator phenotypes have been associated with increased risk for cancers of the bladder and colon, respectively. DAS and DADS decreased the activity of this enzyme in strains of Helicobacter pylori from peptic ulcer patients (Chung et al., 1998) and inhibited its activity in a human colon tumor cell line (Chen et al., 1998) and in human bladder tumor cells (Chung, 1999) in a dose-dependent manner.

1.5. Inhibitions of DNA adduct formation

DNA adducts are believed to be an initial step in carcinogenesis by chemicals. In rat mammary gland, garlic powder decreased the occurrence of 7,12-dimethylbenz[a]anthracene (DMBA)–DNA adducts in vivo and the amounts of total and individual adducts correlated positively with mammary tumor incidence. Garlic powder, garlic water extract, a deodorized garlic powder, a garlic powder with a high sulfur content, and SAC were also effective against mammary DMBA–DNA binding (Amagase and Milner, 1993). DNA adducts induced by incubation of human bladder tumor cells with 2-aminofluorene were inhibited by DAS and DADS (Chung, 1999). In contrast, a water extract of raw garlic and SAC, but not DAS, significantly inhibited benzo[a]pyrene–DNA adduct formation in simulated human peripheral blood lymphocytes in vitro (Hageman et al., 1997). N-Nitroso compounds, a class of potential human carcinogens that can be synthesized in humans from precursors present in the diet, are metabolized to alkylating agents that can bind to DNA. Shenoy and Choughuley (1992) showed that onion and garlic juices inhibit the nitrosation reactions in vitro in a dose-dependent manner. The occurrence of 7-methyldeo-xyguanosine (7-MedG) and O⁶-ethyldeoxyguanosine (O⁶-MedG) was decreased in rat liver when garlic powder was added to a diet containing aminopyrine and sodium nitrite (Lin et al., 1994). Garlic powder also decreased DNA methylation in the livers of rats treated with N-nitrosodimethylamine and in mammary tissue of rats treated with N-methylnitrosourea. Garlic, SAC, and DADS also decreased the formation of 7-MedG and O⁶-MedG induced by N-methylnitrosourea in mammary DNA; this decrease correlated with the inhibition of mammary tumors by these compounds (Schaffer et al., 1996).

1.6. Free-radical scavenging

Free radicals have been related to several age-related diseases, including cancer (Ames et al., 1993). Reduced glutathione (GSH) is not only a cofactor for GST but also serves as a reductant for glutathione peroxidase (GPX), an enzyme involved in natural protection by free radicals, in addition to superoxide dismutase and catalase. Garlic and onion oils stimulated the activity of GPX and inhibited the decreased ratio of reduced to oxidized glutathione produced by 12-O-tetradecanoylphorbol-13-acetate in epidermal cells (Perchellet et al., 1986). GPX activity was also increased in animal tissues with DAS, DADS and garlic oil (Sheen et al., 1999). DAS and DADS also increased the activity of glutathione reductase, and garlic oil increased the activity of superoxide dismutase (Sheen et al., 1999). In contrast, DAS and garlic hom*ogenates decreased catalase in the livers of rats and mice (Chen et al., 1999). S-Allylmercaptosysteine (SAMC) and SAC increased the synthesis of GSH in human prostate cancer cells (Pinto et al., 1997). Aged garlic extract, SAC, and SAMC exhibited radical scavenging activity (Imai et al., 1994). DAS, DADS, and AMS showed selective actions on different markers in tests for their ability to react with carbon tetrachloride de-rived free radicals (Fanelli et al., 1998). DADS also inhibited carbon tetrachloride-induced lipid peroxidation. The antioxidant properties of Allium vegetables might therefore result from the contributions of various sulphur components at different steps of the process.

1.7. Effects on cell proliferation, apoptosis and tumor growth

Inhibition of tumor cell proliferation by organosulfur compounds has been reported in several studies using different cell cultures, including canine mammary tumor cells (Sundaram and Milner, 1993), human colon, lung, and skin tumor cell lines (Sundaram and Milner, 1996; Sakamoto et al., 1997), human neuroblastoma cells (Welch et al., 1992), human and murine melanoma cells (Takeyama et al., 1993), and human prostatic carcinoma cells (Pinto et al., 1997). Contradictory results have been obtained with regard to modulation of the proliferative activity of non-neoplastic cell lines by organosulfur compounds, with some studies showing inhibition (Lee et al., 1994; Seki et al., 2000). Garlic and onion oils caused a marked suppression of proliferation of human promyelocytic leukemia cells (Seki et al., 2000). Garlic powder and an alliin-enriched garlic extract inhibited the growth of a human lymphatic leukemia cell line in a dose-dependent manner, but inhibited the growth of human hepatoma and human colorectal carcinoma cells only when applied as a mixture. This finding indicates that the antiproliferative effect of garlic is due to breakdown pro-ducts of alliin catalyzed by the alliinase enzyme system present in garlic powder (Siegers et al., 1999).

Polyamines, mainly spermine, play an important role in cell division and differentiation. SAMC, but not SAC, has been shown to alter polyamine concentrations in human prostate carcinoma cells, increasing that of spermidine and decreasing those of putrescine and spermine (Pinto et al., 1997). Ornithine decarboxylase, a rate-limiting enzyme involved in the synthesis of polyamines, is also reduced by DAS (Perchellet et al., 1986; Baer and Wargovich, 1989), although there is evidence of an increase in the livers of rat not treated with initiators (Takada et al., 1994). Apoptosis (also known as programmed cell death) is a tightly controlled and evolutionarily conserved process of cellular suicide critical to normal embryonic development and maintenance of tissue homeostasis. Deregulation of programmed cell death underlies numerous pathological conditions including cancer and, therefore, apoptosis is a valid target in cancer therapy and prevention (Kaufmann and Gores, 2000; Ghobrial et al., 2005). The antiproliferative effect of organosulfur compounds appears to be related to the induction of apoptosis. Exposure to DADS and DATS caused cells to undergo apoptosis, as determined by morphologic changes and/or DNA fragmentation (Sundaram and Milner, 1996; Sakamoto et al., 1997). A positive correlation was found between DADS-induced DNA fragmentation and increased intracellular free-calcium concentration, which may activate calcium-dependent endonucleases leading to apoptosis. A study (Hong et al., 2000) showed that DAS, DADS, and garlic extract increase the number of non-small-cell lung cancer cells in the apoptotic state. This increase followed the induction of p53 protein by DADS or the increase of the expression of Bax and decrease of the expression of Bcl-2 by DAS and garlic extract. Ajoene induced apoptosis in human leukemic cells but not in peripheral mononuclear blood cells from healthy donors (Dirsch et al., 1998).

1.8. Inhibition of cell cycle progression

The cell cycle was also affected by DADS, which decreased the percentage of human colon tumor cells in the G₁ and S phases and concomitantly increased the percentage of those in the G₂/M phase (Knowles and Milner, 1998). These effects depended on the dose of DADS and the length of incubation. The ability of DADS to inhibit cell proliferation was related to induction of G₂/M phase arrest and to inhibition of p34^cdc2 kinase activity, which modulates the progression of cells from G₂ into the M phase of the cell cycle. The suppression of the p34^cdc2 kinase activity by DADS resulted not from a direct inter-action with the protein but from modulation of the factors involved in the formation and conversion of the enzyme to its active form (Knowles and Milner, 2000). DADS also significantly inhibited the growth of H-ras oncogene transformed tumors implanted in nude mice by suppressing the association of p21^H-ras with the cell membrane (Singh et al., 1996).

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