Cytofluorescence localization of adriamycin in resistant colon cancer cells.
A simple fluorescent microscopic method demonstrated that adriamycin was distributed in two cellular compartments of living rat colon cancer cells. Adriamycin accumulated slowly in cytoplasmic granules, probably lysosomes, where it persisted long after the drug was removed from the medium. On the other hand, adriamycin accumulated rapidly in the nucleus, but was rapidly cleared in adriamycin-free medium. Drug efflux from the nucleus was blocked by sodium azide in glucose-free medium or by verapamil, a calcium-blocking agent. When colon cancer cells were cultivated for 1 day or longer in adriamycin-containing medium no nuclear fluorescence was observed. However, the addition of sodium azide to glucose-free medium or verapamil restores the nuclear fluorescence. The colon cancer cells had low sensitivity to adriamycin, but the addition of verapamil strongly enhanced adriamycin toxicity. Thus adriamycin is permanently cleared from the nucleus of rat colon cancer cells through an energy-dependent efflux mechanism, which is blocked by verapamil. The efficiency of this efflux mechanism is enhanced by exposure of the cell to adriamycin. This mechanism could be involved in the resistance of colon cancer to adriamycin.
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D004351:Drug Resistance; D006651:Histocytochemistry; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D004317:Doxorubicin; D014700:Verapamil; D013936:Thymidine