Lipid peroxidation and cancer: a critical reconsideration.

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.