Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics

被引:1
作者
Ali, Ahlam A. [1 ]
Cairns, Lauren V. [2 ]
Clarke, Kathryn M. [3 ]
Blayney, Jaine K. [2 ]
Lappin, Katrina M. [2 ]
Mills, Ken I. [2 ]
机构
[1] Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, Sch Med Dent & Biomed Sci, Belfast BT9 7AE, North Ireland
[2] Queens Univ Belfast, Patrick G Johnston Ctr Canc Res, Belfast BT9 7AE, North Ireland
[3] Belfast City Hosp, Haematol Dept, C Floor,Tower Block, Belfast BT9 7AB, North Ireland
关键词
AML; apoptosis; paediatric; drug screening; synergism; double combination; triple combination; phosphoproteomics; ACUTE MYELOID-LEUKEMIA; PHOSPHORYLATION; BAX; BCL-2; AKT; ESTABLISHMENT; PROTEINS; CELLS; MCL-1;
D O I
10.3390/ijms24065717
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no "standard approach" exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted "cell death and survival" as an aberrant, potentially targetable pathway in paediatric AML patients. Therefore, we aimed to identify novel combination therapies to target apoptosis. Our apoptotic drug screening resulted in the identification of one potential "novel" drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines. Using a phosphoproteomic approach to understand the apoptotic mechanism involved, proteins related to apoptotic cell death and cell survival were represented, in agreement with further results showing differentially expressed apoptotic proteins and their phosphorylated forms among combination treatments compared to single-agent treated cells such upregulation of BAX and its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total levels of Bcl-2 were decreased but correlated with increased levels of phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis predictions. Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML.
引用
收藏
页数:22
相关论文
共 45 条
  • [31] Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells
    Papa, V.
    Tazzari, P. L.
    Chiarini, F.
    Cappellini, A.
    Ricci, F.
    Billi, A. M.
    Evangelisti, C.
    Ottaviani, E.
    Martinelli, G.
    Testoni, N.
    McCubrey, J. A.
    Martelli, A. M.
    [J]. LEUKEMIA, 2008, 22 (01) : 147 - 160
  • [32] Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia
    Park, Sophie
    Chapuis, Nicolas
    Tamburini, Jerome
    Bardet, Valerie
    Cornillet-Lefebvre, Pascale
    Willems, Lise
    Green, Alexa
    Mayeux, Patrick
    Lacombe, Catherine
    Bouscary, Didier
    [J]. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 2010, 95 (05): : 819 - 828
  • [33] Phosphorylation of Bcl2 and regulation of apoptosis
    Ruvolo, PP
    Deng, X
    May, WS
    [J]. LEUKEMIA, 2001, 15 (04) : 515 - 522
  • [34] Post-translational modifications of VDAC1 and VDAC2 cysteines from rat liver mitochondria
    Saletti, Rosaria
    Reina, Simona
    Pittala, Maria G. G.
    Magri, Andrea
    Cunsolo, Vincenzo
    Foti, Salvatore
    De Pinto, Vito
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 2018, 1859 (09): : 806 - 816
  • [35] Dissociation of Bax from a Bcl-2/Bax heterodimer triggered by phosphorylation of serine 70 of Bcl-2
    Shitashige, M
    Toi, M
    Yano, T
    Shibata, M
    Matsuo, Y
    Shibasaki, F
    [J]. JOURNAL OF BIOCHEMISTRY, 2001, 130 (06) : 741 - 748
  • [36] Soldovieri M. V., 2009, XPHARM COMPREHENSIVE, P1, DOI [10.1016/B978-008055232-3.63562-7, DOI 10.1016/B978-008055232-3.63562-7]
  • [37] Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia
    Tibes, Raoul
    Bogenberger, James M.
    [J]. FRONTIERS IN ONCOLOGY, 2019, 9
  • [38] Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors Bax and Bak
    Tomiyama, Arata
    Serizawa, Shinobu
    Tachibana, Ken
    Sakurada, Kaori
    Samejima, Hirotsugu
    Kuchino, Yoshiyuki
    Kitanaka, Chifumi
    [J]. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (20): : 1462 - 1473
  • [39] ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor
    Tse, Christin
    Shoemaker, Alexander R.
    Adickes, Jessica
    Anderson, Mark G.
    Chen, Jun
    Jin, Sha
    Johnson, Eric F.
    Marsh, Kerman C.
    Mitten, Michael J.
    Nimmer, Paul
    Roberts, Lisa
    Tahir, Stephen K.
    Mao, Yu
    Yang, Xiufen
    Zhang, Haichao
    Fesik, Stephen
    Rosenberg, Saul H.
    Elmore, Steven W.
    [J]. CANCER RESEARCH, 2008, 68 (09) : 3421 - 3428
  • [40] The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
    van Delft, Mark F.
    Wei, Andrew H.
    Mason, Kylie D.
    Vandenberg, Cassandra J.
    Chen, Lin
    Czabotar, Peter E.
    Willis, Simon N.
    Scott, Clare L.
    Day, Catherine L.
    Cory, Suzanne
    Adams, Jerry M.
    Roberts, Andrew W.
    Huang, David C. S.
    [J]. CANCER CELL, 2006, 10 (05) : 389 - 399