Brief report Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

Recent studies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 path-ways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potenti-ated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobolo-gram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simul-taneous exposure to PD184352 signifi-cantly (P .01) potentiated HA14-1–medi-ated inhibition of clonogenic growth in all primary AML samples tested. These find-ings show that the Bcl-2 and MAPK path-ways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeu-tic strategy for this disease. (Blood. 2002