Subcellular distribution of doxorubicin: comparison of fatty acid-modified and unmodified cells

We have examined the subcellular localization of doxorubicin and evaluated the effect of fatty acid modification on specific intracellular localization. L1210 leukemia cells enriched with docosahexaenoic acid (22:6) or oleic acid (18:1) were incubated with radiolabeled or unlabeled doxorubicin. After equilibration the cells were ruptured and the subcellular fractions were isolated by differential centrifugation and sucrose gradient separation. The doxorubicin localized primarily in nuclei, as expected, but appreciable amounts were also detected in mitochondria and smaller amounts in plasma membranes, microsomes, and cytoplasm. Subcellular distribution of another anticancer drug which binds to DNA, mitoxantrone, was similar. There were increased amounts of doxorubicin contained in the nuclei and all organelles of the 22:6-enriched cells. Although polyunsaturated fatty acid modification influenced the total amount of doxorubicin in fractions, the relative distribution of drug among the fractions was not different from that of the 18:1-enriched and unmodified cells. We conclude that enrichment with polyunsaturates influences total drug uptake but not proportional distribution of doxorubicin.