Cepharanthine, a bisbenzylisoquinoline (biscoclaurine) alkaloid, completely overcomes resistance of a multidrug-resistant subline, Chr-24, derived from human KB carcinoma cells, to vincristine, actinomycin D, and daunomycin, and partially overcomes resistance to Adriamycin. Another biscoclaurine alkaloid, berbamine, partially overcomes resistance to these anticancer agents. Accumulation of [3H]daunomycin in Chr-24 cells is about 10% of that in both the parental KB and revertant cell line (Rev-2) which is derived from Chr-24. Cepharanthine prominently increases the accumulation of daunomycin in resistant Chr-24 cells, but not in parental KB and Rev-2 cells. Enhanced efflux of daunomycin from the resistant cells is completely inhibited by cepharanthine. Cellular uptake of [3H]daunomycin is not significantly affected in the resistant cells by cepharanthine. Accumulation of [3H]cepharanthine is observed at similar levels in both KB and Chr-24. Phosphatidylserine specifically inhibited the accumulation of [3H]cepharanthine in KB and Chr-24 cells when tested by adding various phospholipids such as phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin to culture medium. The enhanced accumulation of [3H]daunomycin in cepharanthine-treated Chr-24 cells in inhibited in the presence of 20 µg/ml phosphatidylserine. Cepharanthine may overcome multidrug resistance by binding to phosphatidylserine in the plasma membrane and perturbing membrane function.

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This work was supported by a grant-in-aid for cancer research from the Ministry of Education, Science, and Culture of Japan.

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