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Targeting p53-MDM2-MDMX Loop for Cancer Therapy

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Mutant p53 and MDM2 in Cancer

Part of the book series: Subcellular Biochemistry ((SCBI,volume 85))

Abstract

The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as “the guardian of the genome”, because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2-MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.

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References

  1. Brown CJ et al (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9(12):862–873

    CAS  PubMed  Google Scholar 

  2. Kruse JP, Gu W (2009) Modes of p53 regulation. Cell 137(4):609–622

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Hollstein M et al (1991) p53 mutations in human cancers. Science 253(5015):49–53

    CAS  PubMed  Google Scholar 

  4. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408(6810):307–310

    CAS  PubMed  Google Scholar 

  5. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431

    CAS  PubMed  Google Scholar 

  6. Hong H et al (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460(7259):1132–1135

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Wu X et al (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7(7A):1126–1132

    CAS  PubMed  Google Scholar 

  8. Momand J et al (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69(7):1237–1245

    CAS  PubMed  Google Scholar 

  9. Barak Y et al (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12(2):461–468

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Shvarts A et al (1996) MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15(19):5349–5357

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Eischen CM, Lozano G (2009) p53 and MDM2: antagonists or partners in crime? Cancer Cell 15(3):161–162

    CAS  PubMed  Google Scholar 

  12. Gu J et al (2002) Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277(22):19251–19254

    CAS  PubMed  Google Scholar 

  13. Haupt Y et al (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299

    CAS  PubMed  Google Scholar 

  14. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387(6630):299–303

    CAS  PubMed  Google Scholar 

  15. Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420(1):25–27

    CAS  PubMed  Google Scholar 

  16. Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96

    CAS  PubMed  Google Scholar 

  17. Gembarska A et al (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18(8):1239–1247

    CAS  PubMed  Google Scholar 

  18. Biderman L et al (2012) MdmX is required for p53 interaction with and full induction of the Mdm2 promoter after cellular stress. Mol Cell Biol 32(7):1214–1225

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Wade M, Wahl GM (2009) Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res 7(1):1–11

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Zhang Y, Lu H (2009) Signaling to p53: ribosomal proteins find their way. Cancer Cell 16(5):369–377

    CAS  PubMed  Google Scholar 

  21. Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 20(5):299–309

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Garcia D et al (2011) Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev 25(16):1746–1757

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Tang Y et al (2008) Acetylation is indispensable for p53 activation. Cell 133(4):612–626

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Shieh SY et al (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91(3):325–334

    CAS  PubMed  Google Scholar 

  25. Banin S et al (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281(5383):1674–1677

    CAS  PubMed  Google Scholar 

  26. Maya R et al (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15(9):1067–1077

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Kapoor M, Lozano G (1998) Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc Natl Acad Sci U S A 95(6):2834–2837

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92(6):725–734

    CAS  PubMed  Google Scholar 

  29. Kobet E et al (2000) MDM2 inhibits p300-mediated p53 acetylation and activation by forming a ternary complex with the two proteins. Proc Natl Acad Sci U S A 97(23):12547–12552

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Li M et al (2002) Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277(52):50607–50611

    CAS  PubMed  Google Scholar 

  31. Ito A et al (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20(6):1331–1340

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Luo J et al (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107(2):137–148

    CAS  PubMed  Google Scholar 

  33. Vaziri H et al (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107(2):149–159

    CAS  PubMed  Google Scholar 

  34. Cheng HL et al (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 100(19):10794–10799

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Luo J et al (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408(6810):377–381

    CAS  PubMed  Google Scholar 

  36. Onel K, Cordon-Cardo C (2004) MDM2 and prognosis. Mol Cancer Res 2(1):1–8

    CAS  PubMed  Google Scholar 

  37. Nosho K et al (2009) SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Mod Pathol 22(7):922–932

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Jung-Hynes B et al (2009) Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem 284(6):3823–3832

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Ozdag H et al (2006) Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics 7:90

    PubMed Central  PubMed  Google Scholar 

  40. Tseng RC et al (2009) Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia 11(8):763–770

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Jones SN et al (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378(6553):206–208

    CAS  PubMed  Google Scholar 

  42. Montes de Oca Luna R, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378(6553):203–206

    CAS  PubMed  Google Scholar 

  43. Gannon HS, Jones SN (2012) Using mouse models to explore MDM-p53 signaling in development, cell growth, and tumorigenesis. Genes Cancer 3(3–4):209–218

    PubMed Central  PubMed  Google Scholar 

  44. Vassilev LT et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848

    CAS  PubMed  Google Scholar 

  45. Chargari C et al (2011) Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Cancer Lett 312(2):209–218

    CAS  PubMed  Google Scholar 

  46. Kojima K et al (2010) The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther 9(9):2545–2557

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Yang Y et al (2005) Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7(6):547–559

    CAS  PubMed  Google Scholar 

  48. Roxburgh P et al (2012) Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis 33(4):791–798

    CAS  PubMed  Google Scholar 

  49. Herman AG et al (2011) Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay. Cancer Discov 1(4):312–325

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Galatin PS, Abraham DJ (2004) A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. J Med Chem 47(17):4163–4165

    CAS  PubMed  Google Scholar 

  51. Lu Y et al (2006) Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy. J Med Chem 49(13):3759–3762

    CAS  PubMed  Google Scholar 

  52. Yin H et al (2005) Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction. Angew Chem Int Ed Engl 44(18):2704–2707

    CAS  PubMed  Google Scholar 

  53. Hardcastle IR et al (2006) Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold. J Med Chem 49(21):6209–6221

    CAS  PubMed  Google Scholar 

  54. Hardcastle IR et al (2011) Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. J Med Chem 54(5):1233–1243

    CAS  PubMed  Google Scholar 

  55. Koblish HK et al (2006) Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5(1):160–169

    CAS  PubMed  Google Scholar 

  56. Schilling D et al (2013) Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered heat shock protein 70 (Hsp70) levels. Cell Stress Chaperones 18(2):183–191

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Cheok CF et al (2011) Translating p53 into the clinic. Nat Rev Clin Oncol 8(1):25–37

    CAS  PubMed  Google Scholar 

  58. Bista M et al (2012) On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS One 7(6):e37518

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Reed D et al (2010) Identification and characterization of the first small molecule inhibitor of MDMX. J Biol Chem 285(14):10786–10796

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Wang H et al (2011) A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol Cancer Ther 10(1):69–79

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Graves B et al (2012) Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A 109(29):11788–11793

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Qin JJ et al (2012) Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. Curr Med Chem 19(33):5705–5725

    CAS  PubMed  Google Scholar 

  63. Zak K et al (2013) Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). Expert Opin Ther Pat 23(4):425–448

    CAS  PubMed  Google Scholar 

  64. Kamal A, Mohammed AA, Shaik TB (2012) p53-Mdm2 inhibitors: patent review (2009–2010). Expert Opin Ther Pat 22(2):95–105

    CAS  PubMed  Google Scholar 

  65. Weber L (2010) Patented inhibitors of p53-Mdm2 interaction (2006–2008). Expert Opin Ther Pat 20(2):179–191

    CAS  PubMed  Google Scholar 

  66. Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90(4):595–606

    CAS  PubMed  Google Scholar 

  67. Gu W, Shi XL, Roeder RG (1997) Synergistic activation of transcription by CBP and p53. Nature 387(6635):819–823

    CAS  PubMed  Google Scholar 

  68. Li L et al (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21(2):266–281

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Zhang Q et al (2012) A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. EMBO Mol Med 4(4):298–312

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Lain S et al (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13(5):454–463

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Kim WJ et al (2012) The WTX tumor suppressor enhances p53 acetylation by CBP/p300. Mol Cell 45(5):587–597

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Kussie PH et al (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274(5289):948–953

    CAS  PubMed  Google Scholar 

  73. Joseph TL et al (2010) Differential binding of p53 and nutlin to MDM2 and MDMX: computational studies. Cell Cycle 9(6):1167–1181

    CAS  PubMed  Google Scholar 

  74. Almerico AM et al (2012) Molecular dynamics studies on Mdm2 complexes: an analysis of the inhibitor influence. Biochem Biophys Res Commun 424(2):341–347

    CAS  PubMed  Google Scholar 

  75. Tsuganezawa K et al (2013) A fluorescent-based high-throughput screening assay for small molecules that inhibit the interaction of MdmX with p53. J Biomol Screen 18(2):191–198

    PubMed  Google Scholar 

  76. Grasberger BL et al (2005) Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 48(4):909–912

    CAS  PubMed  Google Scholar 

  77. Popowicz GM, Domling A, Holak TA (2011) The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. Angew Chem Int Ed Engl 50(12):2680–2688

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Pazgier M et al (2009) Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A 106(12):4665–4670

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Liu M et al (2010) D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms. Proc Natl Acad Sci U S A 107(32):14321–14326

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Zhan C et al (2012) An ultrahigh affinity d-peptide antagonist Of MDM2. J Med Chem 55(13):6237–6241

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Sasiela CA et al (2008) Identification of inhibitors for MDM2 ubiquitin ligase activity from natural product extracts by a novel high-throughput electrochemiluminescent screen. J Biomol Screen 13(3):229–237

    CAS  PubMed  Google Scholar 

  82. Murray MF et al (2007) A high-throughput screen measuring ubiquitination of p53 by human mdm2. J Biomol Screen 12(8):1050–1058

    PubMed  Google Scholar 

  83. Dudgeon DD et al (2010) Implementation of a 220,000-compound HCS campaign to identify disruptors of the interaction between p53 and hDM2 and characterization of the confirmed hits. J Biomol Screen 15(7):766–782

    CAS  PubMed  Google Scholar 

  84. Dudgeon DD et al (2010) Characterization and optimization of a novel protein-protein interaction biosensor high-content screening assay to identify disruptors of the interactions between p53 and hDM2. Assay Drug Dev Technol 8(4):437–458

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Khoury K et al (2011) The p53-MDM2/MDMX axis – a chemotype perspective. Med Chem Commun 2(4):246–260

    CAS  Google Scholar 

  86. Popowicz GM et al (2010) Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle 9(6):1104–1111

    CAS  PubMed  Google Scholar 

  87. Bernal F et al (2007) Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc 129(9):2456–2457

    CAS  PubMed  Google Scholar 

  88. Bernal F et al (2010) A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18(5):411–422

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Huang Y et al (2010) 1,4-Thienodiazepine-2,5-diones via MCR (I): synthesis, virtual space and p53-Mdm2 activity. Chem Biol Drug Des 76(2):116–129

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Lee JH et al (2011) Novel pyrrolopyrimidine-based alpha-helix mimetics: cell-permeable inhibitors of protein-protein interactions. J Am Chem Soc 133(4):676–679

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Czarna A et al (2010) Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. Angew Chem Int Ed Engl 49(31):5352–5356

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Fu T et al (2012) Molecular dynamic simulation insights into the normal state and restoration of p53 function. Int J Mol Sci 13(8):9709–9740

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Ding K et al (2006) Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 49(12):3432–3435

    CAS  PubMed  Google Scholar 

  94. Shangary S et al (2008) Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A 105(10):3933–3938

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Yu S et al (2009) Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J Med Chem 52(24):7970–7973

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Rew Y et al (2012) Structure-based design of novel inhibitors of the MDM2-p53 interaction. J Med Chem 55(11):4936–4954

    CAS  PubMed  Google Scholar 

  97. Lucas BS et al (2012) An expeditious synthesis of the MDM2-p53 inhibitor AM-8553. J Am Chem Soc 134(30):12855–12860

    CAS  PubMed  Google Scholar 

  98. Bowman AL et al (2007) Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. J Am Chem Soc 129(42):12809–12814

    CAS  PubMed  Google Scholar 

  99. Jacoby E et al (2009) Knowledge-based virtual screening: application to the MDM4/p53 protein-protein interaction. Methods Mol Biol 575:173–194

    CAS  PubMed  Google Scholar 

  100. Tovar C et al (2013) MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 73(8):2587–2597

    CAS  PubMed  Google Scholar 

  101. Ray-Coquard I et al (2012) Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 13(11):1133–1140

    CAS  PubMed  Google Scholar 

  102. Andreeff M et al (2012) Results of the phase 1 trial of RG7112, a small-molecule MDM2 antagonist, in acute leukemia. In: 54 annual meeting American Society of Hematology, Atlanta, 8–11 Dec 2012, p 615, Abstract 675

    Google Scholar 

  103. Wang S et al (2012) Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. Top Med Chem 8:57–80

    Google Scholar 

  104. Mohammad RM et al (2009) An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol Cancer 8:115

    PubMed Central  PubMed  Google Scholar 

  105. Menendez S et al (2011) MDM4 downregulates p53 transcriptional activity and response to stress during differentiation. Cell Cycle 10(7):1100–1108

    CAS  PubMed  Google Scholar 

  106. Laurie NA, Schin-Shih C, Dyer MA (2007) Targeting MDM2 and MDMX in retinoblastoma. Curr Cancer Drug Targets 7(7):689–695

    CAS  PubMed  Google Scholar 

  107. Smith MA et al (2012) Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program. Pediatr Blood Cancer 59(2):329–332

    PubMed  Google Scholar 

  108. Honda R, Yasuda H (1999) Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 18(1):22–27

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Weber JD et al (1999) Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1(1):20–26

    CAS  PubMed  Google Scholar 

  110. Kamijo T et al (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95(14):8292–8297

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Bothner B et al (2001) Defining the molecular basis of Arf and Hdm2 interactions. J Mol Biol 314(2):263–277

    CAS  PubMed  Google Scholar 

  112. Sivakolundu SG et al (2008) Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo. J Mol Biol 384(1):240–254

    CAS  PubMed Central  PubMed  Google Scholar 

  113. DiGiammarino EL et al (2001) Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein. Biochemistry 40(8):2379–2386

    CAS  PubMed  Google Scholar 

  114. Weber JD et al (2000) Cooperative signals governing ARF-mdm2 interaction and nucleolar localization of the complex. Mol Cell Biol 20(7):2517–2528

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Zhou X et al (2012) Scission of the p53-MDM2 loop by ribosomal proteins. Genes Cancer 3(3–4):298–310

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Zhang Q et al (2011) Hydrophilic residues are crucial for ribosomal protein L11 (RPL11) interaction with zinc finger domain of MDM2 and p53 protein activation. J Biol Chem 286(44):38264–38274

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Dai MS et al (2006) Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J Biol Chem 281(34):24304–24313

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Bhat KP et al (2004) Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. EMBO J 23(12):2402–2412

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Zhang Y et al (2003) Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol 23(23):8902–8912

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Imai S (2007) Is Sirt1 a miracle bullet for longevity? Aging Cell 6(6):735–737

    CAS  PubMed  Google Scholar 

  121. Chen D et al (2005) Increase in activity during calorie restriction requires Sirt1. Science 310(5754):1641

    CAS  PubMed  Google Scholar 

  122. Stunkel W et al (2007) Function of the SIRT1 protein deacetylase in cancer. Biotechnol J 2(11):1360–1368

    CAS  PubMed  Google Scholar 

  123. Inoue Y et al (2011) Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1. J Biol Chem 286(8):6311–6320

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Chen WY et al (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123(3):437–448

    CAS  PubMed  Google Scholar 

  125. Blum CA et al (2011) SIRT1 modulation as a novel approach to the treatment of diseases of aging. J Med Chem 54(2):417–432

    CAS  PubMed  Google Scholar 

  126. Chakrabarty SP, Balaram H, Chandrasekaran S (2011) Sirtuins: multifaceted drug targets. Curr Mol Med 11(9):709–718

    CAS  PubMed  Google Scholar 

  127. Balcerczyk A, Pirola L (2010) Therapeutic potential of activators and inhibitors of sirtuins. Biofactors 36(5):383–393

    CAS  PubMed  Google Scholar 

  128. Zhang Y et al (2012) Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth. Cancer Biol Ther 13(10):915–924

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Yiwei Z, Zhang Q, Zeng SX, Qian Hao, Hua Lu (2013) Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents. Neoplasia 15(5):523–534

    Google Scholar 

  130. Zhang Q et al (2012) Structure and activity analysis of Inauhzin analogs as novel antitumor compounds that induce p53 and inhibit cell growth. PLoS One 7(10):e46294

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Liao JM et al (2012) Global effect of inauhzin on human p53-responsive transcriptome. PLoS One 7(12):e52172

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Azmi AS et al (2011) Network perspectives on HDM2 inhibitor chemotherapy combinations. Curr Pharm Des 17(6):640–652

    CAS  PubMed  Google Scholar 

  133. Azmi AS et al (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer 46(6):1122–1131

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Zheng T et al (2010) Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways. J Cancer Res Clin Oncol 136(10):1597–1604

    CAS  PubMed  Google Scholar 

  135. Koster R et al (2011) Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis 2:e148

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Michaelis M et al (2011) Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis 2:e243

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Muller PA, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15(1):2–8

    CAS  PubMed  Google Scholar 

  138. Long J et al (2010) Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 116(1):71–80

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Laurie NA et al (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444(7115):61–66

    CAS  PubMed  Google Scholar 

  140. Clegg HV et al (2012) Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction. PLoS One 7(5):e38212

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Huang L et al (2011) The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A 108(29):12001–12006

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Itahana K et al (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12(4):355–366

    CAS  PubMed  Google Scholar 

  143. Di J, Zhang Y, Zheng J (2011) Reactivation of p53 by inhibiting Mdm2 E3 ligase: a novel antitumor approach. Curr Cancer Drug Targets 11(8):987–994

    CAS  PubMed  Google Scholar 

  144. Maslon MM, Hupp TR (2010) Drug discovery and mutant p53. Trends Cell Biol 20(9):542–555

    CAS  PubMed  Google Scholar 

  145. Bykov VJ et al (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288

    CAS  PubMed  Google Scholar 

  146. Mohell N et al (2010) Preclinical efficacy and toxicology studies of APR-246, a novel anticancer compound currently in clinical trials for refractory hematological malignancies and prostate cancer. Blood 116(21)

    Google Scholar 

  147. Lehmann S et al (2012) Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 30(29):3633–3639

    CAS  PubMed  Google Scholar 

  148. Shalom-Feuerstein R et al (2013) Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci U S A 110(6):2152–2156

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Yu X et al (2012) Allele-specific p53 mutant reactivation. Cancer Cell 21(5):614–625

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Lawrence HR et al (2009) Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking. Bioorg Med Chem Lett 19(14):3756–3759

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Parks DJ et al (2005) 1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg Med Chem Lett 15(3):765–770

    CAS  PubMed  Google Scholar 

  152. Zhuang C et al (2012) Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction. J Med Chem 55(22):9630–9642

    CAS  PubMed  Google Scholar 

  153. Krajewski M et al (2005) NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 11(11):1135–1136; author reply 1136–7

    CAS  PubMed  Google Scholar 

  154. Issaeva N et al (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 10(12):1321–1328

    CAS  PubMed  Google Scholar 

  155. Michel J et al (2009) In Silico Improvement of beta3-peptide inhibitors of p53 x hDM2 and p53 x hDMX. J Am Chem Soc 131(18):6356–6357

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Palani CD, Beck JF, Sonnemann J (2012) Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression. Invest New Drugs 30(1):25–36

    CAS  PubMed  Google Scholar 

  157. Zauli G et al (2012) The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status. Haematologica 97(11):1722–1730

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Vatsyayan R et al (2013) Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma. Mol Carcinog 52(1):39–48

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Weisberg E, Sattler M (2012) A novel combination therapy approach for the treatment of acute myeloid leukemia: the multi-kinase inhibitor sorafenib and the HDM2 inhibitor nutlin-3. Haematologica 97(11):1620–1621

    PubMed Central  PubMed  Google Scholar 

  160. Vaseva AV et al (2011) Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis 2:e156

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Zauli G et al (2011) Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. Clin Cancer Res 17(4):762–770

    CAS  PubMed  Google Scholar 

  162. Kurosu T et al (2010) Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. Apoptosis 15(5):608–620

    CAS  PubMed  Google Scholar 

  163. Cheok CF et al (2010) Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ 17(9):1486–1500

    CAS  PubMed  Google Scholar 

  164. Azmi AS et al (2011) MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene 30(1):117–126

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Carter BZ et al (2010) Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML. Blood 115(2):306–314

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Ooi MG et al (2009) Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clin Cancer Res 15(23):7153–7160

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Tabe Y et al (2009) MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res 15(3):933–942

    CAS  PubMed  Google Scholar 

  168. Jin L et al (2010) MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma. Cancer Lett 299(2):161–170

    CAS  PubMed  Google Scholar 

  169. Cross B et al (2011) Inhibition of p53 DNA binding function by the MDM2 protein acidic domain. J Biol Chem 286(18):16018–16029

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Secchiero P et al (2011) Recent advances in the therapeutic perspectives of Nutlin-3. Curr Pharm Des 17(6):569–577

    CAS  PubMed  Google Scholar 

  171. Saha MN et al (2010) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9(11):936–944

    CAS  PubMed  Google Scholar 

  172. McCormack E et al (2012) Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 26(5):910–917

    CAS  PubMed  Google Scholar 

  173. Kojima K et al (2006) Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 5(23):2778–2786

    CAS  PubMed  Google Scholar 

  174. Kojima K et al (2008) 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 112(7):2886–2895

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Kojima K et al (2008) The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 22(9):1728–1736

    CAS  PubMed  Google Scholar 

  176. Ohgami T et al (2010) Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers. Cancer Sci 101(6):1387–1395

    CAS  PubMed  Google Scholar 

  177. Endo S et al (2011) Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. Cancer Sci 102(3):605–613

    CAS  PubMed  Google Scholar 

  178. Mir R et al (2013) Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. Int J Cancer 132(7):1525–1536

    CAS  PubMed  Google Scholar 

  179. D’Anneo A et al (2010) Paclitaxel and beta-lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho-Akt. J Cell Physiol 222(2):433–443

    PubMed  Google Scholar 

  180. Cheok CF, Dey A, Lane DP (2007) Cyclin-dependent kinase inhibitors sensitize tumor cells to nutlin-induced apoptosis: a potent drug combination. Mol Cancer Res 5(11):1133–1145

    CAS  PubMed  Google Scholar 

  181. Hu B et al (2006) MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 281(44):33030–33035

    CAS  PubMed  Google Scholar 

  182. Nadler-Milbauer M et al (2011) Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer. J Drug Target 19(10):859–873

    CAS  PubMed  Google Scholar 

  183. Jones RJ et al (2011) HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma. Blood 118(15):4140–4149

    PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by NIH-NCI grants CA095441, CA 079721, CA129828, and CA172468, as well as the LLL fund to H.L.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Ave, Louisiana, LA, 70112, USA

    Qi Zhang, Shelya X. Zeng & Hua Lu

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  1. Qi Zhang
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  2. Shelya X. Zeng
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  3. Hua Lu
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Correspondence to Hua Lu .

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Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Swati Palit Deb

  2. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Sumitra Deb

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Zhang, Q., Zeng, S.X., Lu, H. (2014). Targeting p53-MDM2-MDMX Loop for Cancer Therapy. In: Deb, S., Deb, S. (eds) Mutant p53 and MDM2 in Cancer. Subcellular Biochemistry, vol 85. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9211-0_16

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