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 [(3)H]-
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.