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rdf:type |
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lifeskim:mentions |
umls-concept:C0007589,
umls-concept:C0007634,
umls-concept:C0018270,
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0023467,
umls-concept:C0037083,
umls-concept:C0040845,
umls-concept:C0086418,
umls-concept:C0205263,
umls-concept:C0237477,
umls-concept:C1280500,
umls-concept:C1414805,
umls-concept:C1511938,
umls-concept:C1710082
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pubmed:issue |
7
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pubmed:dateCreated |
2009-8-5
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pubmed:abstractText |
Our study explored the drug interaction of all-trans retinoic acid (ATRA) and RAD001 (everolimus), the inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in acute myelogenous leukemia (AML) NB4 and HL60 cells. RAD001 (10 nM) significantly enhanced the ATRA-induced growth arrest and differentiation of these cells, as measured by colony-forming assay and cell cycle analysis, and expression of CD11b cell surface antigen and nitroblue tetrazolium reduction, respectively. ATRA (0.1-1 microM) upregulated levels of RTP801, a negative regulator of mTORC1, and inhibited mTORC1 signaling as assessed by measurement of the levels of p-p70S6K and p-4E-BP1 in HL60 and NB4 cells. ATRA (0.1-1 microM) in combination with RAD001 (10 nM) strikingly downregulated the levels of p-70S6K and p-4E-BP1 without affecting the total amount of these proteins. Notably, RAD001 (10 nM) significantly augmented ATRA-induced expression of CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) and p27(kip1) and downregulated levels of c-Myc in these cells. Furthermore, RAD001 (5 mg/kg) enhanced the ability of ATRA (10 mg/kg) to inhibit the proliferation of HL60 cells growing as tumor xenografts in immune-deficient nude mice. Taken together, concomitant blockade of the RA and mTORC1 signaling may be a promising treatment strategy for individuals with AML.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD11b,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/CCAAT-Enhancer-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/CEBPE protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/DDIT4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/ITGAM protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/MYC protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nitroblue Tetrazolium,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-myc,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Retinoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Sirolimus,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tretinoin,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Markers, Biological,
http://linkedlifedata.com/resource/pubmed/chemical/everolimus,
http://linkedlifedata.com/resource/pubmed/chemical/mTORC1 complex, human
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1097-0215
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
125
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1710-20
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:19507250-Animals,
pubmed-meshheading:19507250-Antigens, CD11b,
pubmed-meshheading:19507250-Antineoplastic Agents,
pubmed-meshheading:19507250-Blotting, Western,
pubmed-meshheading:19507250-CCAAT-Enhancer-Binding Proteins,
pubmed-meshheading:19507250-Cell Cycle,
pubmed-meshheading:19507250-Cell Differentiation,
pubmed-meshheading:19507250-Cell Line, Tumor,
pubmed-meshheading:19507250-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:19507250-Down-Regulation,
pubmed-meshheading:19507250-Drug Synergism,
pubmed-meshheading:19507250-Female,
pubmed-meshheading:19507250-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:19507250-HL-60 Cells,
pubmed-meshheading:19507250-Humans,
pubmed-meshheading:19507250-Leukemia, Myeloid, Acute,
pubmed-meshheading:19507250-Mice,
pubmed-meshheading:19507250-Mice, Inbred BALB C,
pubmed-meshheading:19507250-Mice, Nude,
pubmed-meshheading:19507250-Neoplasm Proteins,
pubmed-meshheading:19507250-Nitroblue Tetrazolium,
pubmed-meshheading:19507250-Proteins,
pubmed-meshheading:19507250-Proto-Oncogene Proteins c-myc,
pubmed-meshheading:19507250-Receptors, Retinoic Acid,
pubmed-meshheading:19507250-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:19507250-Signal Transduction,
pubmed-meshheading:19507250-Sirolimus,
pubmed-meshheading:19507250-Transcription Factors,
pubmed-meshheading:19507250-Transplantation, Heterologous,
pubmed-meshheading:19507250-Tretinoin,
pubmed-meshheading:19507250-Tumor Markers, Biological,
pubmed-meshheading:19507250-Tumor Stem Cell Assay,
pubmed-meshheading:19507250-Up-Regulation
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pubmed:year |
2009
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pubmed:articleTitle |
Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells.
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pubmed:affiliation |
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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