Roles Of Oxidative Stress In Multistage Carcinogenesis

Oxidation involves the addition or withdrawal of energy by oxygen from reduced carbon-based molecules. The paradox is that this process of free radical oxidation is both deleterious and life sustaining by being coupled to electron transport in the mitochondria of living cells. Cells using oxygen to generate energy represent a source of oxygen radicals and reactive oxygen systems. The action of carcinogens is often accompanied by oxidation reactions acting on DNA. ROS produced in the body include superoxide, hydroxyl, hydroperoxyl, peroxyl, and alkoxyl radicals. RNS include nitric oxide and the peroxynitrite anion. Food and toxicants are also major sources of ROS and RNS.

Investigations of the carcinogenic effects of oxidative stress have been focused primarily on genotoxicity, but ROS are also known to play a significant role in the promotional stage of carcinogenesis. In particular, several oxidants and free radical generators are tumor promoters. A recent theory1 17 33 on epige-netics also suggests that greater attention must be paid to those multistage processes that do not involve DNA damage. Some reports showed that oxidative stress induced by ROS has been linked to tumor promotion in mouse skin and other tissues.34-36 Many tumor promoters generate ROS, and the involvement of ROS, particularly hydrogen peroxide, in the tumor promotion is supported by both in vivo and in vitro studies.20 34 37 The topical application of tumor promoters to mouse skin results in a distinct increase in the production of hydrogen peroxide in the epidermis, which is correlated with their tumor promoting potential.38

Superoxide radicals are also formed in keratinocytes stimulated with the tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate.39

The generation of oxidative stress is another integral component of the inflammatory response. There is considerable evidence that ROS and RNS are involved in the link between chronic inflammation and cancer.40 Furthermore, tumor promoters and lipopolysaccharide can induce inflammation through the overexpression of COX-2 and iNOS with the generation of ROS and RNS. It was reported that ROS41 and RNS42 also promote cancer through the inhibition of GJIC. As stated above, MMPs have long been implicated in cancer-cell invasion and metastasis, but MMPs are also linked to the tumor promotion process, which may be mediated by ROS.29-32 Thus, the promotional phase of carcinogenesis is a consequence of epigenetic events involving inflammation,1 inhibition of GJIC,22 and activation of MMPs,43 which could be mediated by ROS.

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