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

Michele Milella, Zeev Estrov, Steven M. Kornblau, Bing Z. Carter, Marina Konopleva, Ana Tari, Wendy D. Schober, David Harris, Clinton E. Leysath, Gabriel Lopez-Berestein, Ziwei Huang, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

Abstract

Recent sudies 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 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram 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, simultaneous exposure to PD184352 significantly (P = .01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease.

Original languageEnglish
Pages (from-to)3461-3464
Number of pages4
JournalBlood
Volume99
Issue number9
DOIs
Publication statusPublished - May 1 2002

ASJC Scopus subject areas

  • Hematology

Fingerprint

Dive into the research topics of 'Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia'. Together they form a unique fingerprint.

Cite this