Diet, Gene Expression, and Apoptosis: Clues to Cancer Prevention?

The development of cancer results from the interplay between genetic factors and the environment, and dietary factors have been identified as modulators of almost every step in the process. The complexity of this interplay between genetic factors and the nutritional environment is summarized in Fig. 1. In its initial stage, the development of a tumor requires genetic damage, caused either by endogenous processes or by exogenous compounds that produce mutations or even gene deletions. Free radicals are one of the endogenous mediators of oxidative DNA damage and mutations. They are produced by normal oxidative metabolism in cells, but their production is increased under pathologic conditions such as inflammation. The hydroxyl radical is considered to be the ultimate radical species responsible for DNA damage. There is evidence that the oxidative damage resulting, for example, in 8-oxoguanine and oxidized thymine bases, is involved in cancer induction and progression (1,2). Defense mechanisms protecting the DNA from the free radical attack include the antioxidant enzymes superoxide dismutase, catalase, and peroxidase, which require for their function trace elements such as selenium, zinc, and manganese. Other dietary constituents—for example, vitamin C and E, carotenoids, and flavonoids—also contribute to the antioxidative capacity of a cell or an organism. In addition to those "classical" antioxidants, many other compounds, such as caffeine or diallyl polysulfides from aged garlic extracts (3,4), have been identified as antioxidants. However, under certain conditions and depending on a variety of factors, including the level of intake, antioxidants can also have pro-oxidant properties. In the presence of free transition metals such as iron or copper, oxidative DNA damage can be induced by, for example, ascorbic acid through acceleration of the Fenton reaction (5). The presence of metals has also been shown to accelerate DNA nicking by phenolic antioxidants (6). Another important endogenous mechanism influencing the genetic events involved in turner development is the biomethylation of DNA. About 3% of cytosine residues in mammalian DNA are methylated after replication, most probably to