Mini-reviewMultitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds
Introduction
Allium vegetables have been used in the traditional medicine for centuries [1]. Recent scientific investigations have shown that Allium vegetables and their constituents reduce the risk of cardiovascular disease and diabetes, stimulate immune system, protect against infections, and have anti-aging as well as anti-cancer effects [1], [2], [3], [4]. The anti-cancer effects of Allium vegetables are supported by epidemiological data from population-based case-control studies. For example, You et al. [5] examined the association between Allium vegetable intake and the risk of gastric cancer in a population-based case-control study involving 564 patients and 1131 healthy controls. Subjects in the highest quartile of Allium vegetable intake had significantly lower risk of developing gastric cancer compared to those in the lowest quartile [5]. Similarly, another population-based case-control study conducted in Shanghai, China evaluated the effects of Allium vegetable intake on prostate cancer risk [6]. The results of this study indicated that intake of Allium vegetables was inversely associated with the risk of prostate cancer [6]. While these examples serve to illustrate protective effect of Allium vegetables against cancer risk [5], [6], similar conclusions have been reached for certain other types of cancers in epidemiological studies extensively reviewed by Shukla and Kalra [7]. These epidemiological studies triggered intense research in the past two decades aimed not only at identification of the putative phytochemicals responsible for the anti-cancer effects of Allium vegetables but also elucidation of the mechanism of their action.
Section snippets
Anti-cancer phytochemicals in Allium vegetables
Research over the years has revealed that the anti-cancer effects of Allium vegetables are attributable to organosulfur compounds (OSCs), which are released from the vegetables upon their processing (mincing, chewing etc.) [8]. The γ-glutamyl-S-alk(en)yl-l-cysteines are the primary sulfur compounds in intact Allium vegetables, which are hydrolyzed and oxidized to yield S-alkyl(en)yl-l-cysteine sulfoxide (alliin) [8]. Alliin is the odorless precursor of the OSCs and naturally accumulates during
Modulation of carcinogen metabolism
Carcinogenic chemicals often require metabolic activation mediated by cytochrome P450-dependent monooxygenases (phase 1 enzymes) for their neoplastic activity. Inactivation of activated carcinogenic intermediates is accomplished by phase 2 enzymes including glutathione transferases. Studies have revealed that OSCs can not only inhibit phase 1 enzymes but also increase the expression of phase 2 enzymes (reviewed extensively in [7], [8], [9]). For example, DAS and its metabolites diallyl
In vivo evidence for cancer preventive/therapeutic effects of OSCs
Belman [46] was the first to show inhibition of chemically induced skin carcinogenesis in mice by garlic oil. Inhibition of skin carcinogenesis by ajoene has also been reported [47], Wargovich et al. [48] showed prevention of 1,2-dimethylhydrazine-induced colon cancer by oral gavage of DAS. The DAS administration dramatically inhibited formation of esophageal tumors induced by N-nitrosomethylbenzylamine in rats [49]. Interestingly, DAS was effective if administered during the initiation phase
Clinical trials
Positive results of the in vitro and in vivo studies were followed up in a few intervention trials which examined the chemopreventive effects of Allium vegetable constituents in human population. First double-blind intervention trial examined the effects of high dose of DATS (also known as allitridum; 200 mg/day) and micro-doses of selenium (100 μg every other day) [58]. Both supplements were taken by the intervention group (2526 subjects) for a period of one month, while control group (2507
Bioavailability, pharmacokinetics, and metabolism of the OSCs
One of the key factors affecting the clinical application of OSCs is their bioavailability and plasma concentrations. Analyses of the compounds reveal that one gram of freshly blended garlic can provide up to 2.5 mg of allicin and about 60 μg of SAC [62]. Similarly, it has been estimated that one gram of fresh garlic contains about 900–1100 μg of DATS and 530–610 μg of DADS [7].Thus it is possible that the concentrations of the OSCs needed to bring about cellular responses (e.g., cell cycle arrest
Concluding remarks and future directions
Research over the years has revealed that naturally occurring OSCs target multiple pathways to inhibit growth of cancer cells, which include impairment of carcinogen metabolism, cell cycle arrest, induction of apoptosis, and inhibition of angiogenesis. Because OSCs exhibit other pharmacological effects, such as cardiovascular and anti-microbial effects, these compounds can be classified as being “promiscuous” rather than “selective”. However, promiscuity is not unique to OSCs since many known
Acknowledgement
The work cited in this article from the authors’ laboratory was supported by USPHS Grant CA113363, awarded by the National Cancer Institute.
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