STIMULATION OF 1-(BETA-D-ARABINOFURANOSYL)CYTOSINE (ARAC)-INDUCED APOPTOSIS IN THE MULTIDRUG-RESISTANT HUMAN PROMYELOCYTIC LEUKEMIA-CELL LINES WITH PROTEIN-KINASE INHIBITORS

Stimulation of apoptosis induced by 1-(beta-D-arabinofuranosyl)cytosin e (AraC) with protein kinase inhibitors (i.e. staurosporine, CGP 41 25 1 - a protein kinase C (PKC) - selective staurosporine derivative and protein tyrosine kinase (PKT) inhibitor genistein) was examined in two human multidrug-resistant promyelocytic leukemia (HL-60) cell lines w ith different cell membrane drug resistance-associated glycoproteins ( i.e. HL-60/VCR: MDR1 gene coded Pgp/p170 and HL-60/ADR: MRP gene coded non-Pgp/p190). Staurosporine stimulated AraC-induced apoptosis in the parental drug-sensitive HL-60 cells and both examined multidrug resis tant HL-60 sublines. The stimulation of AraC-induced apoptosis by PKC selective inhibitor CGP 412 251 and PTK-inhibitor genistein was approx imately equal to that of staurosporine in HL-60/ADR cell line. In both parental drug sensitive HL-60 cells and Pgp/p170 positive (MDR1) HL-6 0/VCR, staurosporine-stimulated AraC-induced apoptosis was higher than that stimulated by the PKC selective CGP 41 251 inhibitor, or PTK-inh ibitor genistein. These data suggest that the molecular pathway(s) for AraC-induced apoptosis can be activated and stimulated by PKC- and PT K-inhibitors in both examined drug-resistant HL-60 cell lines. Further more, these data suggest that although both PKC- and PTK-dependent mec hanisms are involved in AraC-induced apoptosis, in the drug-sensitive HL-60 cells and multidrug-resistant HL-60/VCR (Pgp/p170) cells this pr ocess is mediated at least partially, also by PKC- and PTK-independent mechanisms, activated by staurosporine.