Source:http://linkedlifedata.com/resource/pubmed/id/19351820
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
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| pubmed:dateCreated |
2009-4-16
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| pubmed:abstractText |
Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G(0)-G(1) phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3beta. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth.
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| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Furans,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/PI103,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Vincristine
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Apr
|
| pubmed:issn |
1538-7445
|
| pubmed:author | |
| pubmed:issnType |
Electronic
|
| pubmed:day |
15
|
| pubmed:volume |
69
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3520-8
|
| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:19351820-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:19351820-Caspase 3,
pubmed-meshheading:19351820-Caspase 9,
pubmed-meshheading:19351820-Cell Line, Tumor,
pubmed-meshheading:19351820-Drug Synergism,
pubmed-meshheading:19351820-Enzyme Activation,
pubmed-meshheading:19351820-Furans,
pubmed-meshheading:19351820-Humans,
pubmed-meshheading:19351820-Jurkat Cells,
pubmed-meshheading:19351820-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:19351820-Precursor T-Cell Lymphoblastic Leukemia-Lymphoma,
pubmed-meshheading:19351820-Protein Kinase Inhibitors,
pubmed-meshheading:19351820-Protein Kinases,
pubmed-meshheading:19351820-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:19351820-Pyridines,
pubmed-meshheading:19351820-Pyrimidines,
pubmed-meshheading:19351820-Signal Transduction,
pubmed-meshheading:19351820-TOR Serine-Threonine Kinases,
pubmed-meshheading:19351820-Vincristine
|
| pubmed:year |
2009
|
| pubmed:articleTitle |
Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia.
|
| pubmed:affiliation |
Department of Human Anatomical Sciences, University of Bologna, Italy.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|