A historical perspective on garlic and cancer.
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Epidemiological and laboratory studies provide insight into the anticarcinogenic potential of garlic and its constituent compounds. Both water- and lipid-soluble allyl sulfur compounds are effective in blocking a myriad of chemically induced tumors. Part of the protection from these compounds probably relates to a block in nitrosamine formation and metabolism. However, blockage in the initiation and promotion phases of the carcinogenicity of various compounds, including polycyclic hydrocarbons, provide evidence that garlic and its constituents can alter several phase I and II enzymes. Their ability to block experimentally induced tumors in a variety of sites including skin, mammary and colon, suggests a general mechanism of action. Changes in DNA repair and in immunocompetence may also account for some of this protection. Some, but not all, allyl sulfur compounds can also effectively retard tumor proliferation and induce apoptosis. Changes in cellular thiol and phosphorylation stains may account for some of these antitumorigenic properties. The anticarcinogenic potential of garlic can be influenced by several dietary components including specific fatty acids, selenium, and vitamin A. Since garlic and its constituents can suppress carcinogen formation, carcinogen bioactivation, and tumor proliferation it is imperative that biomarkers be established to identify which individuals might benefit most and what intakes can occur with ill consequences. (+info)
Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic.
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Diallyl sulfide (DAS) is a flavor compound derived from garlic and is sequentially converted to diallyl sulfoxide (DASO) and diallyl sulfone (DASO(2)) by cytochrome P(450) 2E1 (CYP2E1). These compounds have been shown to reduce the incidence of a multitude of chemically induced tumors in animal models. The impediment of phase I activation of these carcinogens is hypothesized to be accountable for the reduction in tumor incidence. Indeed, DAS, DASO and DASO(2) are competitive inhibitors of CYP2E1. DASO(2), in addition, is a suicide inhibitor of CYP2E1. These compounds have been shown to reduce carbon tetrachloride-, N-nitrosodimethylamine- and acetaminophen-induced toxicity in rodents. All three chemicals are substrates for CYP2E1. The protective effect was observed when the organosulfur compounds were given before, during or soon after chemical treatment. DAS and DASO(2) inhibited the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related lung tumorigenesis in A/J mice. Because CYP2E1 does not play a key role in NNK activation, the inhibition of other CYP enzymes active in NNK metabolism is likely. DAS also has been shown to induce other CYP and phase II enzymes as well as decrease hepatic catalase activity. All of these effects are observed at concentrations much higher than what is normally ingested by humans. The biological activities of garlic and its related compounds at lower concentrations that mimic human consumption remain to be studied further. (+info)
Impact of garlic organosulfides on p21(H-ras) processing.
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This study describes the novel anticarcinogenic activity of diallyl disulfide, a naturally occurring organosulfide from garlic. Oral administration of diallyl disulfide resulted in a dose-dependent and significant inhibition of the growth of H-ras oncogene transformed NIH 3T3 cells implanted in nude mice. The effect of diallyl disulfide was apparent in terms of delay in the appearance of measurable tumors, tumor volume and tumor weight. On the other hand, the growth of H-ras oncogene transformed tumors was not inhibited by dipropyl disulfide, a naturally occurring saturated analog of diallyl disulfide. The diallyl disulfide-mediated inhibition of H-ras oncogene transformed tumor growth correlated with the inhibition of p21(H-ras) membrane association. The levels of membrane-associated p21(H-ras) were markedly lower in the tumors of diallyl disulfide-treated mice than in those of controls. An opposite trend, however, was evident for the cytosolic p21(H-ras). The results of this study indicate that diallyl disulfide inhibits the growth of H-ras oncogene transformed tumors in vivo by inhibiting the membrane association of p21(H-ras) and that the allyl group may be an important determinant in the inhibitory effect of this organosulfide on tumor growth. (+info)
Antiproliferative effects of allium derivatives from garlic.
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There is increasing evidence that allium derivatives from garlic have significant antiproliferative actions on human cancers. Both hormone-responsive and hormone-unresponsive cells lines respond to these derivatives. The effects shown by allium derivatives include induction of apoptosis, regulation of cell cycle progression and modification of pathways of signal transduction. Allium derivatives appear to regulate nuclear factors involved in immune function and inflammation, as well as in cellular proliferation. Our own studies indicate that allium derivatives inhibit proliferation of the human prostate cancer cell line (LNCaP) and the human breast cancer cell line (MCF-7). Further research is required to clarify the mechanisms of inhibition of cellular proliferation by allium derivatives and to explore their potential application to cancer prevention and control. (+info)
Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation.
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Both oil- and water-soluble allyl sulfur compounds from garlic have been found to possess antitumorigenic properties. These antitumorigenic properties increase as exposure increases both in vitro and in vivo. Generally, oil-soluble allyl sulfur compounds are more effective antiproliferative agents than their water-soluble counterparts. The ability of these compounds to suppress proliferation is associated with a depression in cell cycle progression and the induction of apoptosis. This depression in cell division coincides with an increase in the percentage of cells blocked in the G(2)/M phase of the cell cycle. A depression in p34(cdc2) kinase may account for this blockage in cell division. (+info)
A commentary on the effects of garlic extraction and formulation on product composition.
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The garlic (Allium sativa L.) bulb has been used as a food and condiment for centuries throughout the entire world and in Egypt for perhaps 5000 years. Since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994 by the U.S. Congress, it has been claimed that garlic dietary supplements possess health benefits. Support for this claim is not the primary objective of this publication. The primary objective of this article is to demonstrate that the prediction of a potential health benefit(s) from garlic is largely dependent on the process used to produce a product. (+info)
Mechanism of allyl chloride-induced cytoskeletal injury to nerve cells.
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OBJECTIVE: To dissect the molecular mechanism of toxic neuropathy induced by allyl chloride (AC). METHODS: Fluorescence molecular probe (Fura-2/AM), electron probe X-ray microprobe analysis (EPMA) and biochemical methods were used to determine the concentrations of cytosolic free Ca2+, the contents of intracellular Ca2+ percentage, Ca(2+)-free calmodulin (CaM), the activity of Ca2+/CaM-dependent protein kinase II (Ca2+/CaM-PK II), and cytoskeletal protein synthesis in chicken embryo brain cells induced by AC. RESULTS: The contents of Ca2+ percentage, the concentrations of cytosolic free Ca2+, and the activities of Ca2+/CaM-PK II in the cells were increased significantly as AC was added (P < 0.01). However, the content of Ca(2+)-free CaM and the synthesis of cytoskeletal proteins were markedly decreased (P < 0.01). CONCLUSION: The results suggest that one of the mechanism of AC-induced cytoskeletal injury in vitro might be related to the elevation of intracellular Ca2+, activated CaM and Ca2+/CaM-PK II. (+info)
Sodium salicylate increases CYP2E1 levels and enhances arachidonic acid toxicity in HepG2 cells and cultured rat hepatocytes.
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Sodium salicylate and acetylsalicylic acid are drugs used as anti-inflammatory agents. Salicylate prevents nuclear factor-kappa B activation and can cause apoptosis. However, salicylate, a substrate of CYP2E1, is also an antioxidant and can scavenge reactive oxygen species. Experiments were carried out to evaluate whether salicylate can modulate CYP2E1-dependent toxicity. Addition of a polyunsaturated fatty acid such as arachidonic acid (AA) to HepG2 cells resulted in loss of cell viability, especially in cells expressing CYP2E1 (E47 cells). Toxicity was enhanced by the addition of 1 to 10 mM salicylate to the E47 cells but not to control HepG2 cells or HepG2 cells expressing CYP3A4. Salicylate alone was not toxic, and the enhanced toxicity by AA in the presence of salicylate was prevented by diallyl sulfide, a CYP2E1 inhibitor, and by the antioxidant (+/-)6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. Salicylate potentiated AA-induced lipid peroxidation in the E47 cells, a reaction blocked by diallyl sulfide. CYP2E1 levels were elevated by salicylate at concentrations (<5 mM), which did not increase CYP2E1 mRNA levels. This increase was associated with a decrease of CYP2E1 turnover by salicylate in the presence of cycloheximide. Salicylate also potentiated AA toxicity in hepatocytes isolated from pyrazole treated rats with high levels of CYP2E1 and from saline controls. In view of the potential role of CYP2E1 in contributing to alcohol-induced oxidative stress and liver injury, the potentiation of CYP2E1-dependent toxicity and the elevation of CYP2E1 levels by salicylate may be of clinical significance and merit caution in the use of salicylate and salicylate precursors such as acetylsalicylic acid with certain other drugs. (+info)