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 CCP 41251 significantly enhanced the cytotoxic properties of DXR, actinomycin D, vinblastine, and vincristine but not those of racil. CGP 41251 increased intracellular concentrations of [14C]DXR but did not cause significant differences in P-glycoprotein (P-gp) expression. Pretreatment of MCP-7(adr) 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.
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