Reversal effect of specific inhibitors of extracellular-signal regulated protein kinase pathway on P-glycoprotein mediated vincristine resistance of L1210 cells.
Effect of specific inhibitors of extracellular-signal regulated protein kinase (ERK) pathway, PD98059 and U0126, on P-glycoprotein (Pgp)-mediated vincristine resistance of L1210/VCR cells was investigated. Both test inhibitors significantly reduced the survival of L1210/VCR cells in the presence of vincristine and this was associated with a decrease of LC50 values to vincristine from 2.65+/-0.43 to 0.67+/-0.28 micromol/l and to 0.69+/-0.09 micromol/l after treatment with 50 micromol/l PD98059 and 25 micromol/l UO126, respectively. Moreover, the effects of PD98059 are connected also with an increased intracellular accumulation of radiolabeled vincristine in resistant L1210/VCR cells in concentration dependent manner. The results of this study demonstrate that inhibitors of ERK signaling pathway are reversal agents of vincristine resistance in L1210/VCR cells. The precise mechanism of PD98059 and U0126 action in modulation of MDR is not resolved yet, but the role of ERK-mediated phosphorylation cascade could be considered.
Kisucká
J
J
Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia.
Barancík
M
M
Bohácová
V
V
Breier
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002070:Butadienes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007939:Leukemia L1210; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008956:Models, Chemical; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D014750:Vincristine; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one