Reversal of multidrug resistance by tacrolimus hydrate.

Tacrolimus hydrate, a potent immunosuppressant produced by Streptomyces tsukubaensis, was examined for its effect on epirubicin activity in multidrug-resistant P388 leukemia (P388/R) cells overexpressing P-glycoprotein and the parent (P388/S) cells. In the absence of modulator, the 50% inhibitory concentration for epirubicin after 48-h incubation, determined using a microculture tetrazolium assay, was 0.8 microgram/ml in P388/R cells and 0.009 microgram/ml in P388/S cells. P388/R cells demonstrated a 90-fold reduction in sensitivity to epirubicin. Tacrolimus hydrate (1 and 10 microM) markedly enhanced epirubicin cytotoxicity by 4.2- and 26.7-fold for P388/R cells. A significant increase in LDH release from cells by tacrolimus hydrate was also observed in P388/R cells treated with epirubicin. Tacrolimus hydrate had a marked effect on epirubicin-induced G2/M blockade in the resistant cells. Both tacrolimus hydrate and cyclosporin A dramatically increased the accumulation of epirubicin by the resistant cells, while these compounds had no effect on epirubicin accumulation in the parent cells. Thus, tacrolimus hydrate is able to down-modulate P-glycoprotein-associated resistance through inhibition of P-glycoprotein function, suggesting that the drug may be a candidate for killing drug-resistant tumor cells.