Abstrakt
The aim of our research was to study the effect of mitoxantrone and two protein kinase inhibitors - caffeine (inhibitor of ATM kinase) and U0126 (inhibitor of MEK1/2 kinase) on MOLT-4 and Jurkat leukaemic cell lines. In this work we show that the inhibition of MEK1/2 is associated with an increased mortality of cells after mitoxantrone (MTX) treatment.
Inhibition of ATM by caffeine postponed MTX-induced cell death in MOLT-4 cells. MTX itself induced cell cycle arrest and accumulation of the cells in late S and G2/M phase.
Inhibition of ATM, but not of MEK1/2, abrogated MTX-induced cell cycle arrest. Inhibition of MEK1/2 did not change MTX-induced upregulation of p53 and p21, but inhibition of ATM decreased markedly upregulation of p53 and p21 and p53 phosphorylations on serine 15 and serine 392.
It can be concluded that: 1) MTX-induced phosphorylation of p53 on serine 15 and serine 392 is ATM-dependent and MEK1/2-ERK1/2 independent. 2) ATM inhibition by caffeine prevents G2 cell arrest and in p53 positive cells MOLT-4 delays the onset of MTX-induced cell death. 3) Inhibition of MEK1/2-ERK1/2 cascade potentiates cytostatic effect of MTX regardless of p53 status.