Abstract
Drug resistance remains a major obstacle to successful cancer treatment. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in acute lymphoblastic leukemia (ALL) cells. The screen indicated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity. We tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells and found that it sensitized to GC-induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis and that the combination of rapamycin and glucocorticoids has potential utility in lymphoid malignancies. Furthermore, this approach represents a strategy for identification of promising combination therapies for cancer.
Publication types
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Comparative Study
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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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Cell Line, Tumor
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Cell Survival / drug effects
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Databases, Genetic
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Dexamethasone / pharmacology
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Dose-Response Relationship, Drug
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Drug Combinations
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Drug Resistance, Neoplasm
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Gene Expression / drug effects*
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Genomics*
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Glucocorticoids / pharmacology*
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Green Fluorescent Proteins / metabolism
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Humans
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sirolimus / metabolism*
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Sirolimus / pharmacology
Substances
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Drug Combinations
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Glucocorticoids
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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Green Fluorescent Proteins
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Dexamethasone
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Sirolimus
Associated data
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GEO/GSE5258
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GEO/GSE5820
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GEO/GSE5821
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GEO/GSE5822