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)cytosine (AraC) with protein kinase inhibitors (i.e. staurosporine, CGP 41251-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 with 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 resistant HL-60 sublines. The stimulation of AraC-induced apoptosis by PKC selective inhibitor CGP 412251 and PTK-inhibitor genistein was approximately 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-60/VCR, staurosporine-stimulated AraC-induced apoptosis was higher than that stimulated by the PKC selective CGP 41251 inhibitor, or PTK-inhibitor genistein. These data suggest that the molecular pathway(s) for AraC-induced apoptosis can be activated and stimulated by PKC- and PTK-inhibitors in both examined drug-resistant HL-60 cell lines. Furthermore, these data suggest that although both PKC- and PTK-dependent mechanisms are involved in AraC-induced apoptosis, in the drug-sensitive HL-60 cells and multidrug-resistant HL-60/VCR (Pgp/p170) cells this process is mediated at least partially, also by PKC- and PTK-independent mechanisms, activated by staurosporine.
Hunáková
L
L
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
Suliková
M
M
Duraj
J
J
Sedlák
J
J
Chorváth
B
B
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D019833:Genistein; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D007529:Isoflavones; D003561:Cytarabine; D019833:Genistein; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin