Tumor Cells Daunorubicin-resistant and -sensitive Human and Murine Daunorubicin-produced Nucleolar Protein B23 Translocation in Cyclosporin A and Verapamil Enhancement of Updated Version

It has recently been shown that anthracycline antibiotic-resistant tumor cells are less responsive to daunorubicin-stimulated B23 nucleolar phosphoprotein translocation than drug-sensitive cells. Since cyclosporin A and verapamil reverse primary acquired and secondary cross-resistance to daunorubicin, we investigated the effect of these agents on nucleolar B23 translocation in sensitive and resistant tumors. We compared modi fied to baseline B23 phosphoprotein distribution between predominantly nucleolar, mixed nucleolar-nuclear, or nuclear immunofluorescence using a monoclonal anti-B23 antibody in parental drug-sensitive and multidrugresistant acute lymphatic leukemia and in daunorubicin-sensitive and -resistant murine hepatoma. Our experiments show that cyclosporin A and verapamil alone have no effect on B23 phosphoprotein translocation, but that the addition of either agent to sensitive parental or resistant tumor sublines markedly enhances daunorubicin-stimulated transloca tion. This effect correlates with the correction of impaired daunorubicin inhibition of RNA synthesis by cyclosporin A and verapamil in the resistant sublines. Our observations suggest that nucleolar B23 phospho protein is an important site in the modulation of anthracycline antibiotic antitumor activity.