Evidence that changes in Se-glutathione peroxidase levels affect the sensitivity of human tumour cell lines to n-3 fatty acids

The human lung adenocarcinoma cell line A-427 is significantly more s ensitive to cytotoxic lipid peroxidation products of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than the human lung adenoc arcinoma cell line SK-LU-1, and the glioblastoma cell lines A-172 and U-87 MG. The cytotoxic effect as well as lipid peroxidation were abo lished by vitamin E. The differential sensitivities of the cell lines were not correlated to the levels of lipid peroxidation products (me asured as the end product malondialdehyde), indicating differences in sensitivities to products of lipid peroxidation. The high sensitivit y of A-427 is apparently due to a low level of selenium-dependent glu tathione peroxidase (GSH-Px), because pretreatment with sodium seleni te (250 nM) increased the GSH-Px activity 3- to 4-fold and protected the cells almost completely against the growth inhibitory effect of D HA. Furthermore, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) a seleno-organic GSH-Px mimic, suppressed the cytotoxic action of DHA t o A-427 in a dose dependent manner. Northern analysis demonstrated th at pretreatment with sodium selenite (250 nM) was accompanied by an i ncreased level of GSH-Px mRNA (1.8-fold) in A-427 cells, while the le vel remained unchanged under the same conditions in DHA/EPA-resistant A-172 cells. In addition, the level of selenophosphate synthetase mR NA (SelD), a key intermediate in tRNA(Sec) formation, increased 1.2- to 1.7-fold in A-427 and A-172 cells after pretreatment with sodium s elenite.