Combination of cyclosporin A and buthionine sulfoximine (BSO) as a pharmacological strategy for circumvention of multidrug resistance in small cell lung cancer cell lines selected for resistance to doxorubicin.
The small cell lung cancer (SCLC) cell lines U-1285 and U-1690 were adapted to growth in continuous presence of doxorubicin (Dox). The resulting cell lines U-1285R and U-1690R were investigated with respect to sensitivity to the glutathione (GSH) depleting agent buthionine sulfoximine (BSO) and the immunosuppressant cyclosporin A (CsA) as well as the Dox resistance modifying ability of these agents. The parental U-1285 cells were more sensitive to BSO compared to parental U-1690 and the multidrug resistant (MDR) sublines, whereas no difference in sensitivity to CsA was observed between parental and MDR lines. BSO (10 microM) or CsA (1 microgram/ml) alone were able to partially reverse Dox resistance in the MDR cell lines, CsA being only marginally active in U-1285R cells. However, the combination of these two drugs at the same concentrations completely reversed Dox resistance in the MDR U-1690R cells whereas the combination was less effective in the U-1285R cells. The results demonstrate that a combination of low concentrations of BSO and CsA, only partially active by themselves in modifying Dox resistance, may be used as a pharmacological strategy to increase Dox sensitivity in some MDR SCLC cells.
Larsson
R
R
Department of Clinical Pharmacology, University Hospital, Uppsala University, Sweden.
Bergh
J
J
Nygren
P
P
D000963:Antimetabolites / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000963:Antimetabolites; D003524:Cyclosporins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin