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Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070.
- Source :
- Leukemia (08876924); Mar2008, Vol. 22 Issue 3, p572-577, 6p, 1 Black and White Photograph, 4 Graphs
- Publication Year :
- 2008
-
Abstract
- Small molecule tyrosine kinase inhibitors, such as imatinib, are effective therapies for BCR-ABL-mediated human leukemias. However, clinical drug resistance occurs, which warrants development of alternative and/or complementary therapeutic strategies to target critical downstream signaling molecules. We recently demonstrated that disrupting 14-3-3/ligand association by a peptide-based 14-3-3 competitive antagonist R18 induces significant apoptosis, partially through reactivation of AKT-inhibited proapoptotic FOXO3a, in FGFR1 fusion-transformed hematopoietic cells. Here, we report that targeting 14-3-3 by R18 effectively induced significant apoptosis in Ba/F3 and K562 cells expressing BCR-ABL, similarly through liberation and reactivation of FOXO3a. Moreover, R18 sensitized BCR-ABL-transformed cells to inhibition with MEK1 inhibitor U0126, Bcl-2 inhibitor GX15-070, or mTOR inhibitor rapamycin. Treatment with these reagents potentiated R18-induced reactivation of proapoptotic FOXO3a with enhanced expression of downstream transcription targets p27(kip1) and Bim1. Furthermore, R18-induced apoptotic cell death in cells expressing diverse imatinib-resistant BCR-ABL mutants, including T315I. This inhibition was enhanced by R18 in combination with U0126 and rapamycin. Thus, our findings suggest that targeting 14-3-3 may potentiate the effects of conventional therapy for BCR-ABL-associated hematopoietic malignancies, and overcome drug resistance. [ABSTRACT FROM AUTHOR]
- Subjects :
- CHRONIC myeloid leukemia
RAPAMYCIN
IMMUNOSUPPRESSIVE agents
IMATINIB
PROTEIN-tyrosine kinase inhibitors
ALKANES
AMINO acids
ANTINEOPLASTIC agents
APOPTOSIS
BENZAMIDE
CARRIER proteins
CELLS
CELLULAR signal transduction
COMPARATIVE studies
DOCUMENTATION
DRUG resistance in cancer cells
DRUG synergism
CLINICAL drug trials
HETEROCYCLIC compounds
RESEARCH methodology
MEDICAL cooperation
GENETIC mutation
ORGANIC compounds
PEPTIDES
PROTEINS
RECOMBINANT proteins
RESEARCH
RESEARCH funding
EVALUATION research
PROTEIN kinase inhibitors
CHEMICAL inhibitors
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 22
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 31237620
- Full Text :
- https://doi.org/10.1038/sj.leu.2405064