Journal article
A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma
Blood, Vol.115(4), pp.824-833
Lymphoid Neoplasia
01/28/2010
Handle:
https://hdl.handle.net/2376/105039
PMCID: PMC2941996
PMID: 19965690
Abstract
The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by
MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9
, and
EWS
fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27
Kip1
, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL.
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Details
- Title
- A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma
- Creators
- Ying-Wei Lin - Department of Pediatrics, Hollings Cancer Center, Medical University of South Carolina, CharlestonZanna M Beharry - Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, CharlestonElizabeth G Hill - Divison of Biostatistics and Epidemiology, Hollings Cancer Center, Medical University of South Carolina, CharlestonJin H Song - Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, CharlestonWenxue Wang - Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, CharlestonZuping Xia - Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, CharlestonZhenhua Zhang - Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDPeter D Aplan - Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDJon C Aster - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; andCharles D Smith - Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, CharlestonAndrew S Kraft - Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston
- Publication Details
- Blood, Vol.115(4), pp.824-833
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Series
- Lymphoid Neoplasia
- Publisher
- American Society of Hematology; Washington, DC
- Identifiers
- 99900546551701842
- Language
- English
- Resource Type
- Journal article