Subcellular Distribution of Doxorubicin: Comparison of Fatty Acid-Modified and Unmodified Cells

Abstract

We have examined the subcellular localization of doxorubicin and evaluated the effect of fatty acid modification on specific intracellular localization. L12 10 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: l-enriched and unmodified cells. We conclude that enrichment with polyunsaturates influences total drug uptake but not proportional distribution of doxorubicin.

Development of a bacterial model for studying anthracycline-membrane interactions

“…Such changes have the ability to reduce membrane fluidity and hence limit the passive uptake of doxorubicin. This is in agreement with the study of Bums et al [14] who found that increasing the level of polyunsaturated acyl chains in tumour cells stimulated drug uptake. However, this effect at 6 h may possibly be due to doxorubicin interacting with the membrane and affecting lipid biosynthesis, but after 24 h resistance mechanisms have been induced which may remove doxorubicin and overcome the initial effect.…”

The potential for treatment with dietary long-chain polyunsaturated n-3 fatty acids during chemotherapy

“…It has been suggested that this alteration of membrane permeability may modify the influx and efflux of drugs into and/or out of tumor cells [65], particularly hydrophobic drugs that pass through the membrane by diffusion. In support of this, enrichment of cell membranes with DHA and/or EPA correlates with an increase in the intracellular accumulation and/or retention of chemotherapeutic drugs (doxorubicin, vincristine, mitoxantrone) and enhanced drug cytotoxicity in a variety of tumor cell types [62,[64][65][66]119,120].…”

Coenzyme Q10 for Prevention of Anthracycline-Induced Cardiotoxicity

“…Intracellular anthracyclines are localized primarily in the nucleus of drug-sensitive cancer cells, [115][116][117][118][119] and for doxorubicin, more than 99.7% of the drug within the nucleus is bound to DNA. 120 In contrast to drugsensitive cancer cells, anthracycline-resistant cancer cells take up far less drug, and that which is taken up is localized primarily in the cytoplasm.…”