Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells

Oncotarget

Volumn 6, Issue 31, 2015, Pages 30487-30499

  Carter, Bing Z ^a   Mak, Po Yee ^a   Mak, Duncan H ^a   Ruvolo, Vivian R ^a   Schober, Wendy ^a   McQueen, Teresa ^a   Cortes, Jorge ^b   Kantarjian, Hagop M ^b   Champlin, Richard E ^b   Konopleva, Marina ^a   Andreeff, Michael ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

Author keywords

Bcl 2; Blast crisis CML; Nutlin3a; Quiescent CD34+cells; TKI

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; BCR ABL PROTEIN; CD34 ANTIGEN; CD38 ANTIGEN; NILOTINIB; NUTLIN 3; PROTEIN BCL 2; PROTEIN MCL 1; PROTEIN MDM2; PROTEIN P53; 4-METHYL-N-(3-(4-METHYLIMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL)-3-((4-PYRIDIN-3-YLPYRIMIDIN-2-YL)AMINO)BENZAMIDE; ABT-737; ANTINEOPLASTIC AGENT; BCL2L1 PROTEIN, HUMAN; BCR-ABL1 FUSION PROTEIN, HUMAN; BIPHENYL DERIVATIVE; CD38 PROTEIN, HUMAN; IMATINIB; IMIDAZOLE DERIVATIVE; MDM2 PROTEIN, HUMAN; MEMBRANE PROTEIN; NITROPHENOL; PIPERAZINE DERIVATIVE; PROTEIN BCL X; PROTEIN KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; SULFONAMIDE; TP53 PROTEIN, HUMAN;

APOPTOSIS; ARTICLE; BLAST CELL CRISIS; CELL PROLIFERATION; CHEMOSENSITIZATION; CHRONIC MYELOID LEUKEMIA; CONTROLLED STUDY; DRUG POTENTIATION; HUMAN; HUMAN CELL; INHIBITION KINETICS; LEUKEMIA CELL; PROTEIN EXPRESSION; PROTEIN TARGETING; STEM CELL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; ENZYME ACTIVATION; GENE EXPRESSION REGULATION; METABOLISM; PATHOLOGY; PHYSIOLOGY; TUMOR CELL CULTURE;

ANTIGENS, CD34; ANTIGENS, CD38; ANTINEOPLASTIC AGENTS; APOPTOSIS; BCL-X PROTEIN; BIPHENYL COMPOUNDS; BLAST CRISIS; CELL PROLIFERATION; ENZYME ACTIVATION; FUSION PROTEINS, BCR-ABL; GENE EXPRESSION REGULATION, LEUKEMIC; HUMANS; IMATINIB MESYLATE; IMIDAZOLES; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MEMBRANE GLYCOPROTEINS; NITROPHENOLS; PIPERAZINES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-BCL-2; PROTO-ONCOGENE PROTEINS C-MDM2; PYRIMIDINES; SULFONAMIDES; TUMOR CELLS, CULTURED; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84945532649     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.5890     Document Type: Article

References (53)

1. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O'Brien SG, Stone RM et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002; 99: 3530-3539.
2. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, Barow M, Mountford JC, Holyoake TL Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood. 2006; 107: 4532-4539.
3. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCRABL activity. J Clin Invest. 2011; 121: 396-409.
4. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002; 99: 319-325.
5. Heaney NB, Holyoake TL. Therapeutic targets in chronic myeloid leukaemia. Hematol Oncol. 2007; 25: 66-75.
6. Holtz MS, Forman SJ, Bhatia R. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia. 2005; 19: 1034-1041.
7. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL. Punish the parent not the progeny. Blood. 2005;105: 1862-1866.
8. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999; 94: 2056-2064.
9. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ, Mills AK, Melo JV, White DL et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013; 122: 515-522.
10. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004; 351: 657-667.
11. Savona M, Talpaz M. Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer. 2008; 8: 341-350.
12. Goff DJ, Court Recart A, Sadarangani A, Chun HJ, Barrett CL, Krajewska M, Leu H, Low-Marchelli J, Ma W, Shih AY, Wei J, Zhai D, Geron I et al. A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell Stem Cell. 2013; 12: 316-328.
13. Mak DH, Schober WD, Chen W, Konopleva M, Cortes J, Kantarjian HM, Andreeff M, Carter BZ. Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells. Mol Cancer Ther. 2009; 8: 2509-2516.
14. Mak DH, Wang RY, Schober WD, Konopleva M, Cortes J, Kantarjian H, Andreeff M, Carter BZ. Activation of apoptosis signaling eliminates CD34+ progenitor cells in blast crisis CML independent of response to tyrosine kinase inhibitors. Leukemia. 2012; 26: 788-794.
15. Reddiconto G, Toto C, Palama I, De Leo S, de Luca E, De Matteis S, Dini L, Passerini CG, Di Renzo N, Maffia M, Coluccia AM. Targeting of GSK3beta promotes imatinibmediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells. Blood. 2012; 119: 2335-2345.
16. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood. 2013; 121: 1824-1838.
17. Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD, Snyder DS, Huettner CS, Shultz L, Holyoake T, Bhatia R. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010; 17: 427-442.
18. Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K, Akgul C, Derdak S, Pickl WF, Wacheck V, Selzer E, Monia BP, Moriggl R et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood. 2005; 105: 3303-3311.
19. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J Exp Med. 2000; 191: 977-984.
20. Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Murotani Y, Matsumoto Y, Tanaka H, Strasser A et al. ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol. 2008; 140: 181-190.
21. Kuroda J, Kimura S, Strasser A, Andreeff M, O'Reilly LA, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Tabe Y, Taniwaki M et al. Apoptosis-based dual molecular targeting by INNO-406, a secondgeneration Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007; 14: 1667-1677.
22. Miyashita T, Reed JC Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995; 80: 293-299.
23. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000; 408: 307-310.
24. Yu J, Zhang L. No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell. 2003; 4: 248-249.
25. Vaseva AV, Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009; 1787: 414-420.
26. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009; 458: 1127-1130.
27. Moll UM, Petrenkol O. The MDM2-p53 interaction. Mol Cancer Res. 2003; 1: 1001.
28. Kojima K, Konopleva M, Samudio IJ, Shikami M, CabreiraHansen M, McQueen T, Ruvolo V, Tsao T, Zeng Z, Vassilev LT, Andreeff M. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005; 106: 3150-3159.
29. Kojima K, Konopleva M, Tsao T, Nakakuma H, Andreeff M. Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia. Blood. 2008; 112: 2886-2895.
30. Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood. 2006; 108: 993-1000.
31. Coll-Mulet L, Iglesias-Serret D, Santidrian AF, Cosialls AM, de Frias M, Castano E, Campas C, Barragan M, de Sevilla AF, Domingo A, Vassilev LT, Pons G, Gil J. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006; 107: 4109-4114.
32. Gu L, Zhu N, Findley HW, Zhou M. MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2. Leukemia. 2008; 22: 730-739.
33. Beck Z, Kiss A, Toth FD, Szabo J, Bacsi A, Balogh E, Borbely A, Telek B, Kovacs E, Olah E, Rak K. Alterations of P53 and RB genes and the evolution of the accelerated phase of chronic myeloid leukemia. Leuk Lymphoma. 2000; 38: 587-597.
34. Jiang Q, Crews LA, Barrett CL, Chun HJ, Court AC, Isquith JM, Zipeto MA, Goff DJ, Minden M, Sadarangani A, Rusert JM, Dao KH, Morris SR et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2013; 110: 1041-1046.
35. Goetz AW, van der Kuip H, Maya R, Oren M, Aulitzky WE. Requirement for Mdm2 in the survival effects of BcrAbl and interleukin 3 in hematopoietic cells. Cancer Res. 2001; 61: 7635-7641.
36. Li L, Wang L, Wang Z, Ho Y, McDonald T, Holyoake TL, Chen W, Bhatia R. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012; 21: 266-281.
37. Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O. Enhancement of imatinib-induced apoptosis of BCR/ABLexpressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. Apoptosis. 2010; 15: 608-620.
38. Peterson LF, Mitrikeska E, Giannola D, Lui Y, Sun H, Bixby D, Malek SN, Donato NJ, Wang S, Talpaz M. p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. Leukemia. 2011; 25: 761-769.
39. Konopleva M, Tabe Y, Zeng Z, Andreeff M. Therapeutic targeting of microenvironmental interactions in leukemia: mechanisms and approaches. Drug ResistUpdat. 2009; 12: 103-113.
40. Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle. 2006; 5: 2778-2786.
41. Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer. 2009; 9: 95-107.
42. Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Muller MC, Hofmann WK, Hochhaus A, Ye BH et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med. 2011; 208: 2163-2174.
43. Carter BZ, Mak DH, Wang Z, Ma W, Mak PY, Andreeff M, Davis RE. XIAP downregulation promotes caspasedependent inhibition of proteasome activity in AML cells. Leuk Res. 2013; 37: 974-979.
44. Kojima K, McQueen T, Chen Y, Jacamo R, Konopleva M, Shinojima N, Shpall E, Huang X, Andreeff M. p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1alpha-mediated down-regulation of CXCL12. Blood. 2011; 118: 4431-4439.
45. Jin LH, Tabe Y, Konoplev S, Xu YY, Leysath CE, Lu HB, Kimura S, Ohsaka A, Rios MB, Calvert L, Kantarjian H, Andreeff M, Konopleva M. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol Ca Ther. 2008; 7: 48-58.
46. Tabe Y, Jin L, Iwabuchi K, Wang RY, Ichikawa N, Miida T, Cortes J, Andreeff M, Konopleva M. Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts. Leukemia. 2012; 26: 883-892.
47. Beider K, Darash-Yahana M, Blaier O, Koren-Michowitz M, Abraham M, Wald H, Wald O, Galun E, Eizenberg O, Peled A, Nagler A. Combination of Imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of stroma and targets CML in vitro and in vivo. Mol Cancer Ther. 2014; 13:1155-69
48. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006; 10: 375-388.
49. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435: 677-681.
50. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 2002; 62: 3603-3608.
51. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood. 2002; 99: 3792-3800.
52. Kato H, Kato S, Kumabe T, Sonoda Y, Yoshimoto T, Kato S, Han SY, Suzuki T, Shibata H, Kanamaru R, Ishioka C. Functional evaluation of p53 and PTEN gene mutations in gliomas. Clin Cancer Res. 2000; 6: 3937-3943.
53. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22: 27-55.