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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 :
- Academic Search Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 15781039
- Full Text :
- https://doi.org/10.1038/sj.leu.2403585