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 correlates 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 murine colon adenocarcinoma cells and their doxorubicin (DXR)-selected MDR variants. Nontoxic concentrations of CGP 41251 significantly enhanced the cytotoxic properties of DXR, actinomycin D, vinblastine, and vincristine but not those of 5-fluorouracil. CGP 41251 increased intracellular concentrations of [14C]DXR but did not cause significant differences in P-glycoprotein (P-gp) expression. Pretreatment of MCF-7adr cells with phorbol 12-myristate 13-acetate reduced the CGP 41251 mediated intracellular accumulation of [14C]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 [3H]azidopine for photoaffinity labeling of P-gp. These data provide evidence that CGP 41251 reverses the MDR phenotype by modulating the phosphorylation of P-gp and/or other PKC substrates critical to the maintenance of the MDR phenotype.