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 UO126, 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 mumol/l and to 0.69 +/- 0.09 mumol/l after treatment with 50 mumol/l PD98059 and 25 mumol/l UO126, respectively. Moreover, the effects of PD98059 are connected also with an increased intra,cellular 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 UO126 action in modulation of MDR is not resolved yet, but the role of ERK-mediated phosphorylation cascade could be considered.