EFFECT OF N-6 AND N-3 FATTY-ACIDS ON THE SURVIVAL OF VINCRISTINE SENSITIVE AND RESISTANT HUMAN CERVICAL-CARCINOMA CELLS IN-VITRO

Cis-unsaturated fatty acids of both the n-6 and n-3 series have been s hown to be cytotoxic to a variety of tumor cells in vitro. Both gamma- linolenic acid (GLA) and eicosapentaenoic acid (EPA) can also augment the cytotoxicity of anticancer drugs. But, the effect of various cis-u nsaturated fatty acids on the survival of tumor cells which are resist ant to anticancer drugs has not been studied so far. Docosahexaenoic a cid (DHA) and EPA of the n-3 series and GLA and dihomo-GLA (DGLA) of t he n-6 series were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and resistant (KB-Ch(R)-8-5) human cervical carcinoma (HeLa- variant) cells in vitro. KB-Ch(R)-8-5 was found to be only marginally less sensitive to the cytotoxic actions of all the fatty acids tested except arachidonic acid (AA) compared to KB-3-1. Cyclo-oxygenase inhib itor, indomethacin; lipoxygenase inhibitor, nordihydroguiaretic (NDGA) ; and calmodulin antagonists, trifluoperazine (TFP) and chlorpromazine (CPZ) were found to be ineffective in blocking the cytotoxic action o f GLA, EPA and DHA, the most effective fatty acids, on KB-3-1 cells. T his suggests that prostaglandins, leukotrienes and calmodulin do not h ave any role in the cytotoxic action of GLA, EPA, and DHA. On the othe r hand, the anti-oxidant, vitamin E, and the superoxide anion quencher , superoxide dismutase (SOD), could completely inhibit the cytotoxic a ction of GLA, EPA and DHA indicating a role for free radicals and, in particular, the superoxide anion in this process. This was supported f urther by the observation that GLA, EPA, and DHA can enhance the forma tion of superoxide anion, hydrogen peroxide, and lipid peroxides in KB -3-1 cells. GLA, EPA, and DHA-induced free radical generation and lipi d peroxidation were also inhibited by vitamin E and SOD. These results suggest that GLA, EPA, and DHA are cytotoxic to both vincristine-sens itive and resistant human cervical carcinoma cells and that it is a fr ee radical dependent process.