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.
Beltran
P J
PJ
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Fan
D
D
Fidler
I J
IJ
O'Brian
C A
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004317:Doxorubicin; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin