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Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells.
- Source :
- Leukemia (08876924); Feb2005, Vol. 19 Issue 2, p234-244, 11p
- Publication Year :
- 2005
-
Abstract
- Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting. [ABSTRACT FROM AUTHOR]
- Subjects :
- ARSENIC compounds
APOPTOSIS
LEUKEMIA
CANCER cells
GENETIC transduction
MITOGENS
CELL lines
MITOCHONDRIAL physiology
MITOCHONDRIAL pathology
ANTINEOPLASTIC agents
BIOLOGICAL transport
CHALONES
COMPARATIVE studies
DRUG resistance in cancer cells
DYNAMICS
ENZYME inhibitors
FLAVONOIDS
GENETIC techniques
RESEARCH methodology
MEDICAL cooperation
MITOCHONDRIA
OXIDES
RESEARCH
RNA
TRANSFERASES
EVALUATION research
ACUTE promyelocytic leukemia
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 19
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 15781039
- Full Text :
- https://doi.org/10.1038/sj.leu.2403585