Circumvention of multiple-drug resistance in human cancer cells by thioridazine, trifluoperazine, and chlorpromazine.
Human KB carcinoma cells were selected in four sequential steps for increasing resistance to colchicine and were found to be cross-resistant to multiple drugs. Thioridazine, a phenothiazine calmodulin inhibitor, almost completely reversed the resistance of the multiple-drug-resistant cells to doxorubicin, vinblastine, dactinomycin, and daunorubicin, and partially reversed the resistance to colchicine and vincristine. Other phenothiazine calmodulin inhibitors, trifluoperazine and chlorpromazine, were also found to show similar but somewhat weaker effects on drug resistance. However, a well-known naphthalenesulfonamide derivative calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), could not reverse the drug resistance. Very low accumulation of vincristine or daunorubicin was observed in the multiple-drug-resistant KB cells in comparison with accumulation in the parental KB cells. Increased rate of accumulation of the drugs by thioridazine, trifluoperazine, and chlorpromazine was most prominent in the resistant KB-ChR-24 cells than in KB cells. We have observed enhanced efflux of the drugs from the resistant cells, and thioridazine inhibited this efflux. These studies suggest a role for increased drug efflux in the development of the multiple-drug resistance phenotype in human carcinoma cells.
Akiyama
S
S
Shiraishi
N
N
Kuratomi
Y
Y
Nakagawa
M
M
Kuwano
M
M
D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002746:Chlorpromazine / Q000494:pharmacology*; D003630:Daunorubicin / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D013881:Thioridazine / Q000494:pharmacology*; D014268:Trifluoperazine / Q000494:pharmacology*; D014316:Tritium; D014750:Vincristine / Q000378:metabolism
D002147:Calmodulin; D014316:Tritium; D014268:Trifluoperazine; D014750:Vincristine; D013881:Thioridazine; D002746:Chlorpromazine; D003630:Daunorubicin