The mechanisms of resistance of anthrax lethal toxin (LeTx)-induced cytotoxicity in AML cells. (c2018)

Abstract

Anthrax lethal toxin has recently been established to induce cytotoxicity in acute myeloid leukemia cell lines by the inhibition of the MAPK pathway. The aim of this study was to investigate the mechanisms by which some acute myeloid leukemia cell lines develop resistance to the LeTx-induced inhibition of the MAPK pathway. This was achieved by determining the differences in the Map Kinase pathway between LeTx-sensitive and resistant AML cell lines. In order to determine if autophagy could be affecting a cell lines capability of developing resistance, the autophagy inhibitor chloroquine was used against both sensitive and resistant cell lines. Our data showed that autophagy is a contributing mechanism to the resistance of Mono-Mac-1 and U937 to the LeTx-mediated inhibition of the MAPK pathway. Another potential mechanism of resistance to the inhibition of MEK1/2 is the negative feedback loop initiated by ERK1/2. In order to investigate this mechanism, we tested the effects of the vertical inhibition of the MAPK pathway using both the MEK1/2 inhibitor LeTx and specific ERK inhibitors (VX-11e and SCH772984). Our results indicate that vertical inhibition by SCH772984 rendered the resistant cell lines sensitive to the inhibition of the MAPK-pathway and showed an increased cytotoxic effect once used in combination with anthrax lethal toxin compared to the use of anthrax lethal toxin alone.