PMID- 23919981 OWN - NLM STAT- MEDLINE DCOM- 20140512 LR - 20211203 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 4 IP - 6 DP - 2013 Jun TI - 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. PG - 830-43 AB - 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. FAU - Reikvam, Hakon AU - Reikvam H AD - Section for Hematology, Department of Clinical Science, University of Bergen, Norway. FAU - Nepstad, Ina AU - Nepstad I FAU - Bruserud, Oystein AU - Bruserud O FAU - Hatfield, Kimberley Joanne AU - Hatfield KJ LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine) RN - 0 (Cytokines) RN - 0 (Indazoles) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 0 (RNA, Messenger) RN - 0 (Sulfonamides) RN - 5142-23-4 (3-methyladenine) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - JAC85A2161 (Adenine) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Oncotarget. 2017 Jan 17;8(3):5638-5639. PMID: 28174345 MH - Adenine/analogs & derivatives/pharmacology MH - Adult MH - Aged MH - Aged, 80 and over MH - Bone Marrow Cells/drug effects/metabolism/pathology MH - Cytogenetics MH - Cytokines/metabolism MH - Female MH - Humans MH - Indazoles/pharmacology MH - Leukemia, Myeloid, Acute/*drug therapy/metabolism/pathology MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - Phosphatidylinositol 3-Kinases/genetics/metabolism MH - *Phosphoinositide-3 Kinase Inhibitors MH - Protein Kinase Inhibitors/*pharmacology MH - RNA, Messenger/genetics/metabolism MH - Signal Transduction MH - Sirolimus/analogs & derivatives/pharmacology MH - Stromal Cells/drug effects/metabolism/pathology MH - Sulfonamides/pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism MH - Young Adult PMC - PMC3757241 EDAT- 2013/08/08 06:00 MHDA- 2014/05/13 06:00 PMCR- 2013/06/01 CRDT- 2013/08/08 06:00 PHST- 2013/08/08 06:00 [entrez] PHST- 2013/08/08 06:00 [pubmed] PHST- 2014/05/13 06:00 [medline] PHST- 2013/06/01 00:00 [pmc-release] AID - 971 [pii] AID - 10.18632/oncotarget.971 [doi] PST - ppublish SO - Oncotarget. 2013 Jun;4(6):830-43. doi: 10.18632/oncotarget.971.