Cargando…
Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells
Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757241/ https://www.ncbi.nlm.nih.gov/pubmed/23919981 |
_version_ | 1782282179975315456 |
---|---|
author | Reikvam, Håkon Nepstad, Ina Bruserud, Øystein Hatfield, Kimberley Joanne |
author_facet | Reikvam, Håkon Nepstad, Ina Bruserud, Øystein Hatfield, Kimberley Joanne |
author_sort | Reikvam, Håkon |
collection | PubMed |
description | Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects. |
format | Online Article Text |
id | pubmed-3757241 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-37572412013-09-03 Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells Reikvam, Håkon Nepstad, Ina Bruserud, Øystein Hatfield, Kimberley Joanne Oncotarget Research Papers Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects. Impact Journals LLC 2013-05-11 /pmc/articles/PMC3757241/ /pubmed/23919981 Text en Copyright: © 2013 Reikvam et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Papers Reikvam, Håkon Nepstad, Ina Bruserud, Øystein Hatfield, Kimberley Joanne Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title | Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title_full | Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title_fullStr | Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title_full_unstemmed | Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title_short | Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
title_sort | pharmacological targeting of the pi3k/mtor pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757241/ https://www.ncbi.nlm.nih.gov/pubmed/23919981 |
work_keys_str_mv | AT reikvamhakon pharmacologicaltargetingofthepi3kmtorpathwayaltersthereleaseofangioregulatorymediatorsbothfromprimaryhumanacutemyeloidleukemiacellsandtheirneighboringstromalcells AT nepstadina pharmacologicaltargetingofthepi3kmtorpathwayaltersthereleaseofangioregulatorymediatorsbothfromprimaryhumanacutemyeloidleukemiacellsandtheirneighboringstromalcells AT bruserudøystein pharmacologicaltargetingofthepi3kmtorpathwayaltersthereleaseofangioregulatorymediatorsbothfromprimaryhumanacutemyeloidleukemiacellsandtheirneighboringstromalcells AT hatfieldkimberleyjoanne pharmacologicaltargetingofthepi3kmtorpathwayaltersthereleaseofangioregulatorymediatorsbothfromprimaryhumanacutemyeloidleukemiacellsandtheirneighboringstromalcells |