Diallyl Disulfide Increases Histone Acetylation and P21WAF1 Expression in Human Gastric Cancer Cells In vivo and In vitro

Bo Su

doi:10.4172/2167-0501.1000106

Abstract

Diallyl disulfide (DADS) exerts numerous anticancer effects, involving multiple molecular mechanisms. In particular, DADS has been revealed as a potential inhibitor attenuating histone deacetylase (HDAC) activity, which could aid cancer prevention and therapy by inducing histone hyperacetylation and consequently reactivating epigenetically silenced tumor suppressor genes involved in cancer initiation and progression. In an in vitro study, we demonstrated that DADS increased histones H3 and H4 acetylation in human gastric cancer MGC803 cells in a time-dependent fashion, accompanied by increased p21WAF1 protein levels, which was consistent with G2/M phase cell cycle arrest. DADS also demonstrated dose-dependent antitumor effects in MGC803-xenografted nude mice in vivo, resulting in tumor cells growth inhibition and G2/M phase arrest. Acetylated histones H3 and H4 were up-regulated by administration of DADS in association with elevated p21WAF1 protein expression. There was no evidence of gross toxicity associated with DADS treatment. DADS also preferentially enhanced acetylation of histone H3 relative to histone H4 both in vivo and in vitro. In addition, characteristic features of cell differentiation were observed in xenografted tumor cells. These results suggest that DADS can cause cell cycle arrest and inhibit cell proliferation by inducing hyperacetylation of histones H3 and H4 and increasing p21WAF1 expression in MGC803 cells, which may partly account for its antitumor effects in gastric cancer. These results indicate that DADS may be useful for gastric cancer prevention, and may have important implications for epigenetic therapy by virtue of its ability to modulate histone acetylation.

Highlights

Gastric cancer is a frequently encountered tumor and the second most common cause of cancer deaths worldwide, accounting for almost two-thirds of the cases occurring in developing countries and 42% in China alone
Mouse monoclonal antibodies against p21WAF1, proliferating cell nuclear antigen (PCNA) and HRPconjugated anti-mouse secondary antibody were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, California, USA)
Human gastric cancer MGC803 cells were incubated in medium alone, in medium containing 15, 30 and 60 mg/L Diallyl disulfide (DADS), or in DADS (30 mg/ L)+sodium butyrate (550 mg/L) for 12 h

Summary

Introduction

Gastric cancer is a frequently encountered tumor and the second most common cause of cancer deaths worldwide, accounting for almost two-thirds of the cases occurring in developing countries and 42% in China alone. In 2008, over 70% of new cases and deaths were in developing countries. Diallyl disulfide (DADS) is a major organosulfur constituent derived from garlic and a few other vegetables of the Allium family [4,5]. Epidemiological and laboratory investigations have shown that garlic and its constituents have anticancer effects manifesting as reduced cancer risk, protection against chemically-induced cancer in animal models, and altered biological behavior of tumors. Convincing data have revealed that DADS can exhibit a variety of anticancer effects in diverse cancers by modulating carcinogen metabolism, retarding cell cycle progression, inhibiting cell proliferation, and inducing cell differentiation or apoptosis [6,7]

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