title: Protein kinase inhibitor-induced alterations of drug uptake, cell cycle and surface antigen expression in human multidrug-resistant (Pgp and MRP) promyelocytic leukemia HL-60 cells.
abstract: Protein kinase inhibitors staurosporine and CGP 41251, a benzoylated derivative of staurosporine with selective PKC inhibitory activity, reversed the decreased rhodamine 123 uptake in HL-60/VCR (with Pgp-mediated drug resistance) but not in HL-60/ADR (MRP-mediated drug resistance) cells. CGP 41251 reversed the decreased rhodamine 123 uptake in HL-60/VCR cells more efficiently (when compared on a equimolar basis) than staurosporine. However, the protein tyrosine kinase inhibitor genistein unexpectedly modulated the decreased rhodamine 123 uptake in Pgp positive (HL-60/VCR) cells, but not in HL-60/ADR (MRP positive) cells. Cell surface phenotype of both HL-60 drug-resistant cell sublines was compared with that of the parental, drug-sensitive HL-60 cells. Both drug-resistant cell lines expressed markedly decreased levels of cell surface HLA class I antigen in comparison with the parental HL-60 cells. A similar decreased cell surface expression of HLA class II/DR on both drug-resistant, as well as of CD59 (protectin) on HL-60/ADR cells was found. Both protein kinase C inhibitors studied (staurosporine and CGP 41251) exhibited variable effects on cell surface antigen (HLA, ICAM-1, CD59) expression, suggesting complex interactions between PKC-dependent and -independent mechanisms in the regulation of surface antigen expression in these cell lines. Staurosporine differed from CGP 41251 in the cell cycle alterations induced in the HL-60 cell lines examined. Staurosporine induced the accumulation of cells in the G2/M phase of the cell cycle and the appearance of pre-G0 (apoptotic) cells in both examined drug-resistant cell lines. Staurosporine induced the appearance of cells with high DNA content in HL-60/ADR, but not in HL-60/VCR cells.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: J
authors.initials: J
authors.lastname: Sedlák
authors.forename: L
authors.initials: L
authors.lastname: Hunáková
authors.forename: M
authors.initials: M
authors.lastname: Suliková
authors.forename: B
authors.initials: B
authors.lastname: Chorváth
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D018957:CD59 Antigens / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007529:Isoflavones / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D014750:Vincristine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000970:Antineoplastic Agents; D018957:CD59 Antigens; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D019833:Genistein; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D018799:Intercellular Adhesion Molecule-1; D007529:Isoflavones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D020112:Rhodamine 123; D012235:Rhodamines; D019311:Staurosporine; D014750:Vincristine; C059539:midostaurin