Effect of Polyunsaturated Fatty Acids and Their Metabolites on Bleomycin-Induced Cytotoxic Action on Human Neuroblastoma Cells In Vitro

In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs) tested on human neuroblastoma IMR-32 (0.5x10(4) cells/100 mu l of IMR) cells (EPA> DHA> ALA=GLA=AA> DGLA=LA: similar to 60, 40, 30, 10-20% respectively) at the maximum doses used. Of all the prostaglandins (PGE(1), PGE(2), PGF(2 alpha), and PGI2) and leukotrienes (LTD4 and LTE4) tested; PGE(1), PGE(2) and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A(4) (LXA(4)), 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA) and 10(S), 17(S)-dihydroxy-4Z, 7Z, 11E, 13Z, 15E, 19Z-docosahexaenoic acid (protectin: 10(S), 17(S) DiHDoHE), metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA) at 60 and 20 mu g/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions.