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

Protein kinase inhibitors staurosporine and CGP 41 251,a benzoylated d erivative of staurosporine with selective PKC inhibitory activity, rev ersed the decreased rhodamine 123 uptake in HL-60/VCR (with Pgp-mediat ed drug resistance) but not in HL-60/ADR (MRP-mediated drug resistance ) cells. CGP 41 251 reversed the decreased rhodamine 123 uptake in HL- 60/VCR cells more efficiently (when compared on a equimolar basis) tha n staurosporine. However, the protein tyrosine kinase inhibitor genist ein unexpectedly modulated the decreased rhodamine 123 uptake in Pgp p ositive (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 d rug-resistant cell lines expressed markedly decreased levels of cell s urface HLA class I antigen in comparison with the parental HL-60 cells . A similar decreased cell surface expression of HLA class II/DR on bo th drug-resistant, as well as of CD59 (protectin) on HL-60/ADR cells w as found. Both protein kinase C inhibitors studied (staurosporine and CGP 41 251) exhibited variable effects on cell surface antigen (HLA, I CAM-1, CD59) expression, suggesting complex interactions between PKC-d ependent and -independent mechanisms in the regulation of surface anti gen expression in these cell lines. Staurosporine differed from CGP 41 251 in the cell cycle alterations induced in the HL-60 cell lines exa mined. Staurosporine induced the accumulation of cells in the G(2)/M p hase of the cell cycle and the appearance of pre-G(0) (apoptotic) cell s in both examined drug-resistant cell lines. Staurosporine induced th e appearance of cells with high DNA content in HL-60/ADR, but not in H L-60/VCR cells. (C) 1997 Elsevier Science Ltd.