ENHANCEMENT OF DOXORUBICIN CYTOTOXICITY BY POLYUNSATURATED FATTY-ACIDS IN THE HUMAN BREAST-TUMOR CELL-LINE MDA-MB-231 - RELATIONSHIP TO LIPID-PEROXIDATION

Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti-cancer drugs. In this study, we examined whether lipid peroxid ation is a potential mechanism through which fatty acids enhance drug cytotoxicity. We measured cell viability in the human breast cancer ce ll line MDA-MB-231 exposed to doxorubicin in the presence of non-cytot oxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids t ested, docosahexaenoic acid (DHA, 22:6n-3) was the most potent in incr easing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10(-7) M doxorubicin alone to 21% when cells were incu bated with doxorubicin and DHA. After addition of an oxidant system (s odium ascorbate/2-methyl-1,4-naphthoquinone) to cells incubated with d oxorubicin and DHA, cell viability further decreased to 12%. Cell hydr operoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid pe roxidation inhibitor (dl-cw-tocopherol) or when oleic acid (a non-pero xidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low pel-oxidation-generating potenti al. Thus, DHA may increase the efficacy of oxyradical-producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents. (C) 1998 Wiley-Liss, Inc.