Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole

This study demonstrates that astemizole, a non-sedating anti-histaminergic drug with low toxicity in vivo, greatly potentiates the growth-inhibitory a ctivity of doxorubicin in doxorubicin-resistant human leukemia cells (K562/ DXR). Astemizole synergistically potentiated the cytotoxicity of doxorubici n for K562/DXR cells at a concentration of 0.1-3 mu M in a dose-dependent m anner, whereas they showed hardly any synthergistic effect in the parental cell line (K562) at the same concentration. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycopro tein, we evaluated the effect of astemizole on P-glycoprotein activity in c ytofluorographic efflux experiments with doxorubicin. Our results indicate that astemizole inhibits the P-glycoprotein pump-efflux activity in a dose- related manner. Moreover, it also inhibits the photolabeling of P-glycoprot ein by [H-3]azidopine in a dose-dependent manner. These findings provide a biological basis for the potential therapeutic application of astemizole as an anticancer drug either alone or in combination with doxorubicin to mult idrug-resistant leukemic cells.