title: PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment.
abstract: Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here, we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions. Hypoxia caused degradation of Mcl-1 and rendered Mcl-1-overexpressing OCI-AML3 cells sensitive to ABT-737. Our findings suggest that pharmacologic PI3K inhibition by GDC-0941 enhances ABT-737-induced leukemia cell death even under the protective conditions afforded by the bone marrow microenvironment.
  
  
  CONCLUSIONS
  Combined blockade of PI3K and Bcl-2 pathways down-regulates anti-apoptotic Mcl-1 expression PI3K and Bcl-2 induced Mcl-1 down-regulation activates BAX PI3K and Bcl-2 blockage induces apoptosis in AML under hypoxic BM microenvironment.
authors: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors: Linhua
authors: L
authors: Jin
authors: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Yoko
authors: Y
authors: Tabe
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Kensuke
authors: K
authors: Kojima
authors: Department of Hematology, Aichi Medical University, Aichi, Japan.
authors: Masato
authors: M
authors: Shikami
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Julina
authors: J
authors: Benito
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Vivian
authors: V
authors: Ruvolo
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Rui-Yu
authors: RY
authors: Wang
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Teresa
authors: T
authors: McQueen
authors: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Stefan O
authors: SO
authors: Ciurea
authors: Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Miida
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Michael
authors: M
authors: Andreeff
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Marina
authors: M
authors: Konopleva
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C501332:ABT-737; D001713:Biphenyl Compounds; D007191:Indazoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D013449:Sulfonamides
references: J Clin Oncol. 2011 Feb 10;29(5):591-9
references: 21220598
references: J Med Chem. 2008 Sep 25;51(18):5522-32
references: 18754654
references: PLoS One. 2012;7(2):e31366
references: 22393362
references: Oncogene. 2007 Jun 7;26(27):3941-51
references: 17213816
references: Genes Dev. 2012 Jan 15;26(2):120-5
references: 22279045
references: Adv Enzyme Regul. 1984;22:27-55
references: 6382953
references: Cancer Res. 2007 Apr 1;67(7):2908-11
references: 17409392
references: Cancer Res. 2001 Mar 15;61(6):2429-33
references: 11289110
references: Cancer Cell. 2006 Nov;10(5):375-88
references: 17097560
references: Mol Cancer Res. 2012 Mar;10(3):347-59
references: 22241218
references: Oncogene. 2010 Feb 4;29(5):625-34
references: 19946328
references: Cancer Cell. 2012 Feb 14;21(2):227-39
references: 22340595
references: BMC Cancer. 2012 Oct 10;12:463
references: 23046567
references: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10853-8
references: 18664580
references: J Clin Oncol. 2012 Mar 10;30(8):765-6
references: 22271482
references: Nature. 2005 Jun 2;435(7042):677-81
references: 15902208
references: Cancer Res. 2007 Jan 15;67(2):782-91
references: 17234790
references: Cancer Cell. 2006 Nov;10(5):389-99
references: 17097561
references: Leukemia. 2010 Jan;24(1):33-43
references: 19946262
references: Blood. 2008 Nov 1;112(9):3538-40
references: 18948586
references: Leukemia. 2010 Aug;24(8):1397-405
references: 20535152
references: Cancer Lett. 2011 Oct 1;309(1):27-36
references: 21664043
references: Nat Rev Cancer. 2002 Jul;2(7):489-501
references: 12094235
references: Mol Cell. 2006 Mar 17;21(6):749-60
references: 16543145
references: Cell Death Differ. 2009 Mar;16(3):360-7
references: 18806758
references: J Clin Invest. 2011 Mar;121(3):1075-87
references: 21393866
references: Cancer Lett. 2006 Oct 28;242(2):231-8
references: 16427189
references: Leukemia. 2012 Apr;26(4):778-87
references: 22064351
references: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1111-6
references: 19144925
references: PLoS One. 2011;6(8):e23108
references: 21853076
references: Leukemia. 2002 Sep;16(9):1713-24
references: 12200686
references: Mol Cancer. 2003 Apr 17;2:23
references: 12740039
references: Cancer Res. 2013 Feb 15;73(4):1340-51
references: 23243017
references: Nat Rev Cancer. 2002 Sep;2(9):647-56
references: 12209154
references: Blood. 2006 Oct 1;108(7):2358-65
references: 16763210
references: Mol Pharmacol. 2007 Sep;72(3):788-95
references: 17595328
references: Blood. 2010 Feb 18;115(7):1416-24
references: 20008792
references: Cancer Biol Ther. 2012 Aug;13(10):858-70
references: 22785211
references: Cancer Res. 2007 Jan 15;67(2):684-94
references: 17234779