Abstract
Activation of the mTOR pathway subsequent to phosphatase and tensin homolog (PTEN) mutation may be associated with glucocorticoid (GC) resistance in acute lymphoblastic leukemia (ALL). The combination activity of rapamycin and dexamethasone in cell lines and xenograft models of ALL was determined. Compared with either drug alone, dexamethasone+rapamycin showed significantly greater apoptosis and cell cycle arrest in some cell lines, and was more frequently seen in T-lineage cell lines with PTEN mutation. The combination significantly extended the event-free survival of mice carrying PTEN mutated xenografts. Our data suggest that PI3K/mTOR pathway inhibitors could benefit patients with PTEN mutated T-ALL.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects*
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Blotting, Western
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Cell Cycle Checkpoints / drug effects*
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Cell Line, Tumor
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Dexamethasone / administration & dosage
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Drug Synergism
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Enzyme-Linked Immunosorbent Assay
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Female
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Flow Cytometry
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Humans
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In Vitro Techniques
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mutation / genetics
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Sirolimus / administration & dosage
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
Substances
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RNA, Messenger
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Dexamethasone
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MTOR protein, human
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Sirolimus