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.
abstract: 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.
authors.affiliation: Section for Hematology, Department of Clinical Science, University of Bergen, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Reikvam
authors.forename: Ina
authors.initials: I
authors.lastname: Nepstad
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.forename: Kimberley Joanne
authors.initials: KJ
authors.lastname: Hatfield
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003582:Cytogenetics; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000225:Adenine; D016207:Cytokines; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D020123:Sirolimus; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C025946:3-methyladenine; C401859:temsirolimus; C546842:MTOR protein, human
references.citation: Oncotarget. 2010 Jun;1(2):156-60
references.pmid: 21297225
references.citation: J Clin Oncol. 2005 Feb 20;23(6):1109-17
references.pmid: 15718307
references.citation: PLoS One. 2013;8(1):e54918
references.pmid: 23349989
references.citation: Eur J Haematol. 2003 Jan;70(1):43-52
references.pmid: 12631258
references.citation: Br J Haematol. 2012 Jan;156(2):205-12
references.pmid: 22082314
references.citation: Leukemia. 2007 Jan;21(1):44-52
references.pmid: 16990761
references.citation: Eur J Haematol. 2005 Jan;74(1):24-34
references.pmid: 15613103
references.citation: Curr Cancer Drug Targets. 2005 Jun;5(4):229-48
references.pmid: 15975045
references.citation: Oncotarget. 2012 Apr;3(4):371-94
references.pmid: 22564882
references.citation: J Biol Chem. 2010 Apr 2;285(14):10850-61
references.pmid: 20123989
references.citation: Blood. 2010 Sep 9;116(10):1747-54
references.pmid: 20522712
references.citation: Curr Protoc Bioinformatics. 2008 Mar;Chapter 7:Unit 7.3
references.pmid: 18428687
references.citation: Curr Top Microbiol Immunol. 2010;341:149-72
references.pmid: 20376612
references.citation: Br J Haematol. 2012 Feb;156(4):468-80
references.pmid: 22150087
references.citation: Oncotarget. 2012 Aug;3(8):811-23
references.pmid: 22885370
references.citation: Oncotarget. 2011 Jun;2(6):510-7
references.pmid: 21680954
references.citation: Oncotarget. 2012 Nov;3(11):1416-27
references.pmid: 23232026
references.citation: Curr Top Microbiol Immunol. 2010;341:59-80
references.pmid: 20373091
references.citation: J Hematother Stem Cell Res. 2002 Jun;11(3):469-81
references.pmid: 12183832
references.citation: Expert Opin Investig Drugs. 2010 Feb;19(2):169-83
references.pmid: 20050812
references.citation: Haematologica. 2010 May;95(5):819-28
references.pmid: 19951971
references.citation: Bone Marrow Res. 2012;2012:329061
references.pmid: 23082251
references.citation: Biochem Biophys Res Commun. 2006 Oct 27;349(3):1003-10
references.pmid: 16959214
references.citation: J Clin Oncol. 2011 Feb 10;29(5):487-94
references.pmid: 21220605
references.citation: Leukemia. 2012 Jun;26(6):1195-202
references.pmid: 22143671
references.citation: Leukemia. 2008 Feb;22(2):287-93
references.pmid: 17943167
references.citation: Curr Med Chem. 2010;17(36):4448-61
references.pmid: 21062258
references.citation: Curr Oncol Rep. 2012 Apr;14(2):129-38
references.pmid: 22350330
references.citation: Oncotarget. 2012 Dec;3(12):1615-28
references.pmid: 23271044
references.citation: Int J Cancer. 2006 Nov 15;119(10):2313-21
references.pmid: 16921487
references.citation: J Hematother Stem Cell Res. 1999 Aug;8(4):431-41
references.pmid: 10634181
references.citation: Eur J Haematol. 2010 Mar;84(3):239-51
references.pmid: 19922462
references.citation: Br J Haematol. 2009 Jan;144(1):53-68
references.pmid: 19016730
references.citation: Curr Med Chem. 2011;18(18):2715-26
references.pmid: 21649579
references.citation: Lancet Oncol. 2011 Mar;12(3):263-72
references.pmid: 21345726
references.citation: Blood. 2007 Apr 15;109(8):3509-12
references.pmid: 17179228
references.citation: Haematologica. 2004 Apr;89(4):391-402
references.pmid: 15075072
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6732-9
references.pmid: 19843663
references.citation: Clin Cancer Res. 2012 Jan 1;18(1):161-9
references.pmid: 22065081
references.citation: Haematologica. 2007 Mar;92(3):332-41
references.pmid: 17339182
references.citation: Am J Hematol. 2012 Jan;87(1):89-99
references.pmid: 22180162
references.citation: J Cancer Res Clin Oncol. 2005 Jun;131(6):377-84
references.pmid: 15776274
references.citation: Oncotarget. 2010 Jun;1(2):89-103
references.pmid: 20671809
references.citation: Hematology Am Soc Hematol Educ Program. 2011;2011:1-8
references.pmid: 22160005
references.citation: Blood. 2004 Dec 15;104(13):4181-7
references.pmid: 15304393
references.citation: J Immunol. 2012 Oct 15;189(8):4154-64
references.pmid: 22972931
references.citation: Clin Cancer Res. 2012 Mar 15;18(6):1716-25
references.pmid: 22167413
references.citation: Leuk Lymphoma. 2005 Jun;46(6):885-91
references.pmid: 16019534
references.citation: Haematologica. 2003 Apr;88(4):416-28
references.pmid: 12681969
references.citation: J Hematother Stem Cell Res. 2000 Dec;9(6):923-32
references.pmid: 11177606
references.citation: Clin Cancer Res. 2006 Nov 15;12(22):6826-35
references.pmid: 17121904
references.citation: Haematologica. 2013 Jan;98(1):57-64
references.pmid: 22801959
references.citation: Mol Cell. 2006 Apr 21;22(2):159-68
references.pmid: 16603397
references.citation: Expert Opin Investig Drugs. 2009 Apr;18(4):433-55
references.pmid: 19335274
references.citation: Eur J Haematol. 2012 Dec;89(6):478-90
references.pmid: 23046151
references.citation: Biochem Biophys Res Commun. 2008 Dec 5;377(1):187-90
references.pmid: 18831964
references.citation: Eur J Clin Invest. 2009 May;39(5):395-405
references.pmid: 19320940
references.citation: Br J Pharmacol. 2013 Jan;168(1):163-71
references.pmid: 22817685
references.citation: Blood. 2012 Sep 27;120(13):2679-89
references.pmid: 22826565