CHEMOSENSITIZATION OF CANCER-CELLS BY THE STAUROSPORINE DERIVATIVE CGP-41251 IN ASSOCIATION WITH DECREASED P-GLYCOPROTEIN PHOSPHORYLATION

The multidrug resistance (MDR) phenotype of cancer cells often correla tes with the level and activity of protein kinase C (PKC). We studied the ability of the staurosporine derivative PKC inhibitor CGP 41251 to reverse the MDR phenotype in MCF-7 human breast carcinoma and CT-26 m urine colon adenocarcinoma cells and their doxorubicin (DXR)-selected MDR variants. Nontoxic concentrations of CGP 41251 significantly enhan ced the cytotoxic properties of DXR, actinomycin D, vinblastine, and v incristine but not those of 5-fluorouracil. CGP 41251 increased intrac ellular concentrations of [C-14]DXR but did not cause significant diff erences in P-glycoprotein (P-gp) expression. Pretreatment of MCF-7(adr ) cells with phorbol 12-myristate 13-acetate reduced the CGP 41251-med iated intracellular accumulation of [C-14]DXR. At concentrations that induced drug uptake, CGP 41251 significantly decreased the level of P- gp phosphorylation in the cells but did not compete with [H-3]azidopin e for photoaffinity labeling of P-gp. These data provide evidence that CGP 41251 reverses the MDR phenotype by modulating the phosphorylatio n of P-gp and/or other PKC substrates critical to the maintenance of t he MDR phenotype. Copyright (C) 1996 Elsevier Science Inc.