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Differential Subcellular Distribution of Mitoxantrone in Relation to Chemosensitization in Two Human Breast Cancer Cell Lines

Institut National de la Santé et de la Recherche Médicale, E 0211, "Nutrition, Croissance et Cancer," Tours, F-37000 France; Université François-Rabelais, Tours, F-37000 France; l'Institut Fédératif de Recherches 135 "Imagerie Fonctionnelle," Tours, F-37000 France (S.V., K.M., J.G., P.B.); and Université François-Rabelais, Faculté de Pharmacie, "Focalisation magnétique d'agents anticancéreux," Tours, F-37200 France; l'Institut Fédératif de Recherches 135 "Imagerie Fonctionnelle," Tours, F-37200 France (P.D., I.C.)

The present work investigates the relationship between cancer cell chemosensitivity and subcellular distribution, molecular interaction, and metabolism of an anticancer drug. To get insights into this relationship, we took advantage of the differential sensitivity of two breast cancer cell lines, MDA-MB-231 and MCF-7, to anthracyclines, along with the property of docosahexaenoic acid (DHA, 22:6n-3), to differentially enhance their cytotoxic activity. The fluorescent drug mitoxantrone (MTX) was used because of the possibility to study its subcellular accumulation by confocal spectral imaging (CSI). The use of CSI allowed us to obtain semiquantitative maps of four intracellular species: nuclear MTX bound to DNA, MTX oxidative metabolite in endoplasmic reticulum, cytosolic MTX, and finally, MTX in a low polarity environment characteristic of membranes. MDA-MB-231 cells were found to be more sensitive to MTX (IC₅₀ = 18 nM) than MCF-7 cells (IC₅₀ = 196 nM). According to fluorescence levels, the nuclear and cytosolic MTX content was higher in MCF-7 than in MDA-MB-231 cells, indicating that mechanisms other than nuclear MTX accumulation account for chemosensitivity. In the cytosol, the relative proportion of oxidized MTX was higher in MDA-MB-231 (60%) than in MCF-7 (7%) cells. DHA sensitized MDA-MB-231 (4-fold) but not MCF-7 cells to MTX and increased MTX accumulation by 1.5-fold in MDA-MB-231 cells only. The DHA-stimulated accumulation of MTX was attributed mainly to the oxidative metabolite. Antioxidant N-acetyl-L-cysteine inhibited the DHA effect on both metabolite accumulation and cell sensitization to MTX. We conclude that drug metabolism and compartmentalization are associated with cell chemosensitization, and the related cytotoxicity mechanisms may involve oxidative stress.