Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 305-314
Cancer Letters

Mini-review
Multitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds

https://doi.org/10.1016/j.canlet.2008.05.027Get rights and content

Abstract

Allium vegetables, such as garlic, have been used for medicinal purposes throughout the recorded history. The known health benefits of Allium vegetables constituents include cardiovascular effects, improvement of the immune function, lowering of blood glucose level, radioprotection, protection against microbial infections, and anti-cancer effects. Initial evidence for the anti-cancer effect of Allium vegetables was provided by population-based case-control studies. Subsequent laboratory studies showed that the Allium vegetable constituents, such as diallyl disulfide, S-allylcysteine, and ajoene can not only offer protection against chemically induced cancer in animal models by altering carcinogen metabolism, but also suppress growth of cancer cells in culture and in vivo by causing cell cycle arrest and apoptosis induction. Suppression of angiogenesis and experimental metastasis by Allium constituents has also been reported. Defining the mechanism by which sulfur compounds derived from Allium vegetables inhibit cancer cell growth has been the topic of intense research in the last two decades. Some Allium vegetable constituents have also entered clinical trials to assess their safety and anti-cancer efficacy. This article summarizes preclinical and limited clinical data to warrant further clinical evaluation of Allium vegetable constituents for prevention and therapy of human cancers.

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.

References (66)

  • S.V. Singh et al.

    Novel anti-carcinogenic activity of an organosulfide from garlic: inhibition of H-RAS oncogene transformed tumor growth in vivo by diallyl disulfide is associated with inhibition of p21H-ras processing

    Biochem. Biophys. Res. Commun.

    (1996)
  • S. Tanaka et al.

    Aged garlic extract has potential suppressive effect on colorectal adenomas in humans

    J. Nutr.

    (2006)
  • K.C. Agarwal

    Therapeutic actions of garlic constituents

    Med. Res. Rev.

    (1996)
  • J.A. Milner

    Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation. Garlic and carcinogenesis

    Adv. Exp. Med. Biol.

    (2001)
  • W.C. You et al.

    Allium vegetables and reduced risk of stomach cancer

    J. Natl. Cancer Inst.

    (1989)
  • A.W. Hsing et al.

    Allium vegetables and risk of prostate cancer: a population-based study

    J. Natl. Cancer Inst.

    (2002)
  • E. Block

    The chemistry of garlic and onions

    Sci. Am.

    (1985)
  • A. Herman-Antosiewicz et al.

    Molecular targets of cancer chemoprevention by garlic-derived organosulfides

    Acta Pharmacol. Sin.

    (2007)
  • J.F. Brady et al.

    Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites

    Chem. Res. Toxicol.

    (1991)
  • V.L. Sparnins et al.

    Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione-S-transferase activity in the mouse

    Carcinogenesis

    (1988)
  • L.M. Knowles et al.

    Diallyl disulfide inhibits p34(cdc2) kinase activity through changes in complex formation and phosphorylation

    Carcinogenesis

    (2000)
  • A. Arunkumar et al.

    Garlic compound, diallyl disulfide induces cell cycle arrest in prostate cancer cell line PC-3

    Mol. Cell. Biochem.

    (2006)
  • J.P. Yuan et al.

    [Diallyl disulfide-induced G2/M arrest of human gastric cancer MGC803 cells involves activation of p38 MAP kinase pathways]

    Ai Zheng

    (2004)
  • J. Antosiewicz et al.

    c-Jun NH(2)-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells

    Cancer Res.

    (2006)
  • A. Herman-Antosiewicz et al.

    Activation of a novel ataxia-telangiectasia mutated and Rad3 related/checkpoint kinase 1-dependent prometaphase checkpoint in cancer cells by diallyl trisulfide, a promising cancer chemopreventive constituent of processed garlic

    Mol. Cancer Ther.

    (2007)
  • D. Xiao et al.

    Diallyl trisulfide-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc 25 C

    Oncogene

    (2005)
  • H. Shirin et al.

    Antiproliferative effects of S-allylmercaptocysteine on colon cancer cells when tested alone or in combination with sulindac sulfide

    Cancer Res.

    (2001)
  • D. Xiao et al.

    Induction of apoptosis by the garlic-derived compound S-allylmercaptocysteine (SAMC) is associated with microtubule depolymerization and c-Jun NH(2)-terminal kinase 1 activation

    Cancer Res.

    (2003)
  • M. Li et al.

    Antitumor activity of Z-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties

    Carcinogenesis

    (2002)
  • K. Hirsch et al.

    Effect of purified allicin, the major ingredient of freshly crushed garlic, on cancer cell proliferation

    Nutr. Cancer

    (2000)
  • S.G. Sundaram et al.

    Diallyl disulfide induces apoptosis of human colon tumor cells

    Carcinogenesis

    (1996)
  • Y.S. Hong et al.

    Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines

    Exp. Mol. Med.

    (2000)
  • S. Karmakar et al.

    Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cells

    Apoptosis

    (2007)
  • Cited by (0)

    View full text