Document Detail


Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells.
MedLine Citation:
PMID:  17549349     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
gamma-Secretase inhibitors (GSI) suppress the growth of acute T-lymphoblastic leukemia (T-ALL) cells with NOTCH1 mutations. Recently, clinical trials of GSI for refractory T-ALL have commenced. In the present study, we examined the effects of three types of GSI; GSI-I, GSI-IX, and GSI-XII on the growth of four B-cell malignant lymphoma (B-ML) and four acute myeloid leukemia (AML) cell lines as well as four T-ALL cell lines. We found that GSI also suppressed the in vitro growth of some B-ML and AML cell lines in a dose-dependent manner. Growth suppression occurred through induction of apoptosis. Expression of the HES1 gene, one of the targets of Notch signaling, was high in T-ALL cells with NOTCH1 mutations, but was low in GSI-sensitive B-ML and AML cells. GSI treatment decreased HES1 mRNA expression in T-ALL cells, while GSI increased HES1 mRNA in two GSI-sensitive B-ML and AML cell lines. In immunoblot analysis, the band for the intracellular fragment of Notch1, an active form of Notch1, was dense in T-ALL cells but was faint in GSI-sensitive B-ML and AML cells; attenuation of the band by GSI was not evident. These findings suggest that GSI may act on Notch 2, 3 or 4 protein, or some pathways other than Notch signaling in GSI-sensitive B-ML and AML cells. Namely, growth suppression by GSI may involve cell growth-related proteins, which are gamma-secretase substrates. Taken together, we have shown that GSI may be useful for the treatment of hematological malignancies other than T-ALL. The mechanism behind the effects remains to be clarified. Our investigations lead to a novel molecular target therapy for chemotherapy-resistant leukemia and lymphomas.
Authors:
Hanae Kogoshi; Taku Sato; Takatoshi Koyama; Nobuo Nara; Shuji Tohda
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology reports     Volume:  18     ISSN:  1021-335X     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-05     Completed Date:  2007-08-16     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  77-80     Citation Subset:  IM    
Affiliation:
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Apoptosis / drug effects
Cell Proliferation / drug effects*
Enzyme Inhibitors / pharmacology*
Humans
Leukemia, Myeloid, Acute / drug therapy,  metabolism,  pathology*
Lymphoma, B-Cell / drug therapy*,  metabolism
Lymphoma, Large B-Cell, Diffuse / drug therapy,  metabolism
Mutation / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy,  metabolism,  pathology*
Receptors, Notch / genetics,  metabolism
Signal Transduction
Tumor Cells, Cultured / drug effects
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Receptors, Notch; EC 3.4.-/Amyloid Precursor Protein Secretases

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