Modification by brefeldin A, bafilomycin A1 and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD) of cellular accumulation and intracellular distribution of anthracyclines in the non-P-glycoprotein-mediated multidrug-resistant cell line COR-L23/R.
We have investigated the effects of H(+)-ATPase inhibitors, bafilomycin A1 and 7-chloro-4-nitro-benz-2-oxa-1,3 diazole (NBD), and the Golgi inhibitor, brefeldin A, on daunorubicin accumulation and doxorubicin intracellular distribution in the non-P-glycoprotein-mediated multidrug-resistant cell line COR-L23/R. This cell line overexpress a 190 kDa protein which is probably the product of the MRP gene and shows an anthracycline accumulation defect and a drastically altered intracellular anthracycline distribution from the parental cell line COR-L23/P. We found that all three agents could selectively increase the cellular accumulation of daunorubicin in resistant cells. However, these effects were only seen at doses of the modifiers which were equal to or greater than the IC50 of the modifier alone. Effects of the modifiers on the intracellular distribution of doxorubicin fluorescence could, however, be seen at doses lower than those required to produce significant effects on daunorubicin accumulation. However, when used in a continuous MTT chemosensitivity assay none of the agents, used at maximum non-toxic doses, was able to sensitise COR-L23/R cells to doxorubicin or to colchicine. Although these lead compounds are unlikely to be useful as clinical modifiers, development of more selective analogues may prove useful in the modification of non-P-glycoprotein-mediated multidrug resistance.
Rhodes
T
T
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
Barrand
M A
MA
Twentyman
P R
PR
D009327:4-Chloro-7-nitrobenzofurazan / Q000494:pharmacology* / Q000633:toxicity; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D020126:Brefeldin A; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002352:Carrier Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology* / Q000633:toxicity; D003593:Cytoplasm / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D006056:Golgi Apparatus / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D018942:Macrolides; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000633:toxicity; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D003517:Cyclopentanes; D018942:Macrolides; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C057620:bafilomycin A; D020126:Brefeldin A; D004317:Doxorubicin; D006180:Proton-Translocating ATPases; D009327:4-Chloro-7-nitrobenzofurazan; C022616:thiazolyl blue; D003630:Daunorubicin