Polyunsaturated Fatty Acid-Induced Cytotoxicity Against Tumor Cells and Its Relationship to Lipid Peroxidation

Abstract

The contribution of lipid peroxidation to the killing of human breast cancer cells by gamma-linolenate (GLA) was examined. Other fatty acids of different cytotoxic potential containing 2, 4, 5, and 6 double bonds were also tested for comparison. It was found that the cytotoxic potential varied with the ability of the fatty acids to stimulate the production of superoxide radicals. Neither hydrogen peroxide nor hydroxy radicals are significantly involved in cell killing. As nonspecific indicators of lipid peroxidation, measurements of the loss of unsaturated fatty acid in the phospholipids together with the generation of hydroperoxide breakdown products were done with the use of the thiobarbituric acid test. The results of these experiments showed that the effectiveness of a given fatty acid in killing cancer cells correlated with the intracellular thiobarbituric acid-reactive material (TBARM) content: GLA and arachidonate with 3 and 4 double bonds generated the most TBARM and were the most cytotoxic fatty acids, whereas docosahexaenoate with 6 double bonds was the least effective either in raising TBARM or in killing the malignant cells. Iron and copper accelerated the rate of cell death, whereas antioxidants such as vitamin E and butylated hydroxyanisole inhibited the effect of GLA dose dependently. Indomethacin, an inhibitor of endoperoxide formation, did not reduce either cell kill or TBARM amounts. In contrast, the addition of vitamin E acetate to the cancer cell cultures challenged with eicosapentaenoate reduced both cell killing and TBARM content. These results suggest that the effectiveness of a given fatty acid in killing cancer cells correlated with the extent of lipid peroxidation of the added fatty acid in the cells.

Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines

“…The cyclo-oxygenase inhibitors piroxicam and indomethacin had no effect ( Figure 5). As proposed previously by Begin et al (1988) andCanuto et al (1991), this suggests that an oxidative process is involved in the effects of PUFAs on malignant cell lines rather than a cyclo-oxygenase-generated product. The inhibition of growth of the pancreatic cancer cell lines observed in the present study occurred at lower concentrations of PUFA than others have described with different, non-pancreatic, malignant cell lines (Dippenaar et al, 1982;Fugiwara et al, 1983;Begin et al, 1985Begin et al, , 1986Begin et al, , 1988Canuto et al, 1991), indicating that pancreatic cancer cells may be particularly sensitive to the effects of PUFAs, at least in vitro.…”

“…The fact that similar levels of lipid peroxidation were present in circumstances which could result in such different extents of growth inhibition and loss of cell viability suggests that lipid peroxidation may not be the only factor involved in PUFA-induced cell death. Begin et al (1988), using a similar method of measuring lipid peroxidation in a breast cancer cell line, were able to show a correlation between the extent of cell death induced by various fatty acids and the levels of lipid peroxide generated. They also demonstrated that vitamin E inhibited both lipid peroxide formation and PUFA-induced loss of cell viability and that the antiproliferative effects of the PUFA gamma-linoleic acid could be enhanced using pro-oxidants.…”

“…Moreover, the effects of PUFAs have been shown to be selective for cancer cells without affecting normal cells in vitro (Begin et al, 1986). Although enhanced lipid peroxidation has been proposed as one of the main mechanisms by which PUFAs inhibit tumour cell growth in vitro (Begin et al, 1988), it is not clear whether this is the case with all cell lines, nor is it known which peroxidation products are important in tumour cell killing.…”

“…In addition, a variety of antioxidants such as vitamin E, oleic acid and sodium selenite (Begin et al, 1988) have been shown to decrease the anti-cancer effects of PUFAs in vitro. Since these antioxidants are often present in vivo, such findings bring into question whether PUFAs might be effective anticancer agents in patients.…”

Reduced tumour growth of the human colonic cancer cell lines COLO-320 and HT-29 in vivo by dietary n-3 lipids

“…The mechanism of action of fish oil remains to be elucidated. Possibilities include inhibition of cyclo-oxygenase systems (Culp et al, 1979;Corey et al, 1983) and increased lipid peroxidation (Begin & Das, 1986;Begin & Ells, 1987;Begin et al, 1986Begin et al, , 1988Cheeseman et al, 1986). Moreover, in investigating these mechanisms it will be necessary to determine whether the effects are due to a specific n-3 fatty acid and conversely whether similar effects are obtained with n-6 fatty acids.…”