Phytochemical Induction of Cell Cycle Arrest by Glutathione Oxidation and Reversal by N-Acetylcysteine in Human Colon Carcinoma Cells

• Published in: Nutrition and cancer Vol. 61; no. 3; pp. 332 - 339
• Main Authors: Odom, R.Y, Dansby, M.Y, Rollins-Hairston, A.M, Jackson, K.M, Kirlin, W.G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Taylor & Francis Group 07.05.2009; Taylor& Francis
• Subjects: acetylcysteine; Acetylcysteine - pharmacology; Allyl Compounds - pharmacology; Anticarcinogenic Agents - pharmacology; benzyl isothiocyanate; Biological and medical sciences; buthione sulfoxamine; Butyrates - pharmacology; Carotenoids - pharmacology; cell cycle; Cell Cycle - drug effects; cell growth; cell proliferation; Cell Proliferation - drug effects; colorectal neoplasms; diallyl disulfide; Dimethyl Fumarate; disease prevention; Disulfides - pharmacology; Feeding. Feeding behavior; Fumarates - pharmacology; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; glutathione; Glutathione - metabolism; HT29 Cells; human diseases; Humans; inhibitors; intracellular glutathione; Isothiocyanates - pharmacology; Lycopene; Medical sciences; N-acetylcysteine; oxidation; Oxidation-Reduction; phytochemicals; Plants - chemistry; redox potential; sodium butyrate; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Phytochemical compound; Human; Thiol; Induction; Acetylcysteine; Malignant tumor; Colonic disease; Mucolytic; Cancerology; Cell cycle; Digestive diseases; Intestinal disease; Oxidation; Colon carcinoma; Cell; Cancer; Glutathione
• ISSN: 0163-5581; 1532-7914
• DOI: 10.1080/01635580802549982

Cancer prevention by dietary phytochemicals has been shown to involve decreased cell proliferation and cell cycle arrest. However, there is limited understanding of the mechanisms involved. Previously, we have shown that a common effect of phytochemicals investigated is to oxidize the intracellular glutathione (GSH) pool. Therefore, the objective of this study was to evaluate whether changes in the glutathione redox potential in response to dietary phytochemicals was related to their induction of cell cycle arrest. Human colon carcinoma (HT29) cells were treated with benzyl isothiocyanate (BIT) (BIT), diallyl disulfide (DADS), dimethyl fumarate (DMF), lycopene (LYC) (LYC), sodium butyrate (NaB) or buthione sulfoxamine (BSO, a GSH synthesis inhibitor) at concentrations shown to cause oxidation of the GSH: glutathione disulfide pool. A decrease in cell proliferation, as measured by [3H]-thymidine incorporation, was observed that could be reversed by pretreatment with the GSH precursor and antioxidant N-acetylcysteine (NAC). Cell cycle analysis on cells isolated 16 h after treatment indicated an increase in the percentage (ranging from 75-30% for benzyl isothiocyanate and lycopene, respectively) of cells at G2/M arrest compared to control treatments (dimethylsulfoxide) in response to phytochemical concentrations that oxidized the GSH pool. Pretreatment for 6 h with N-acetylcysteine (NAC) resulted in a partial reversal of the G2/M arrest. As expected, the GSH oxidation from these phytochemical treatments was reversible by NAC. That both cell proliferation and G2/M arrest were also reversed by NAC leads to the conclusion that these phytochemical effects are also mediated, in part, by intracellular oxidation. Thus, one potential mechanism for cancer prevention by dietary phytochemicals is inhibition of the growth of cancer cells through modulation of their intracellular redox environment.