Advertisement

Second-Generation Proteasome Inhibitors

  • Dixie-Lee Esseltine
  • Larry Dick
  • Erik Kupperman
  • Mark Williamson
  • Kenneth C. Anderson
Chapter
Part of the Milestones in Drug Therapy book series (MDT)

Abstract

The first-in-class proteasome inhibitor, bortezomib, has provided proof-of-concept for the therapeutic approach of proteasome inhibition in a number of malignancies. However, as we look to the future and to further improving upon the contributions of this class of drugs, we will need to consider optimizing activity in solid tumors, reducing peripheral neuropathy and utilizing more convenient routes of administration. A number of “second-generation” proteasome inhibitors have been identified and are now in preclinical and clinical development, including MLN9708, CEP-18770, carfilzomib, and salinosporamide A (NPI-0052). These agents differ from bortezomib in some of their key characteristics, and differences in their pharmacology may result in different activity and safety profiles. This chapter reviews the second-generation proteasome inhibitors, together with other potential therapeutic targets in the ubiquitin–proteasome system.

Keywords

Multiple Myeloma Proteasome Inhibitor Mantle Cell Lymphoma Proteasome System Multiple Myeloma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360PubMedCrossRefGoogle Scholar
  2. 2.
    Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5:417–421PubMedCrossRefGoogle Scholar
  3. 3.
    Adams J, Kauffman M (2004) Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22:304–311PubMedCrossRefGoogle Scholar
  4. 4.
    Ciechanover A (1998) The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 17:7151–7160PubMedCrossRefGoogle Scholar
  5. 5.
    Ciechanover A, Schwartz AL (1998) The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci U S A 95:2727–2730PubMedCrossRefGoogle Scholar
  6. 6.
    Hershko A (2005) The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12:1191–1197PubMedCrossRefGoogle Scholar
  7. 7.
    Goldberg AL, Elledge SJ, Harper JW (2001) The cellular chamber of doom. Sci Am 284:68–73PubMedCrossRefGoogle Scholar
  8. 8.
    Nencioni A, Grunebach F, Patrone F, Ballestrero A, Brossart P (2007) Proteasome inhibitors: antitumor effects and beyond. Leukemia 21:30–36PubMedCrossRefGoogle Scholar
  9. 9.
    Myung J, Kim KB, Crews CM (2001) The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev 21:245–273PubMedCrossRefGoogle Scholar
  10. 10.
    Kisselev AF, Goldberg AL (2001) Proteasome inhibitors: from research tools to drug candidates. Chem Biol 8:739–758PubMedCrossRefGoogle Scholar
  11. 11.
    Adams J, Behnke M, Chen S et al (1998) Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 8:333–338PubMedCrossRefGoogle Scholar
  12. 12.
    Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622PubMedGoogle Scholar
  13. 13.
    Millennium Pharmaceuticals Inc. (2009) VELCADE® (bortezomib) for Injection. Prescribing information. Cambridge, MA. Issued December 2009, Rev 10Google Scholar
  14. 14.
    Wilk S, Orlowski M (1983) Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex. J Neurochem 40:842–849PubMedCrossRefGoogle Scholar
  15. 15.
    Adams J (2003) The proteasome: structure, function, and role in the cell. Cancer Treat Rev 29(Suppl 1):3–9PubMedCrossRefGoogle Scholar
  16. 16.
    Groll M, Berkers CR, Ploegh HL, Ovaa H (2006) Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14:451–456PubMedCrossRefGoogle Scholar
  17. 17.
    Richardson PG, Mitsiades C, Schlossman R et al (2008) Bortezomib in the front-line treatment of multiple myeloma. Expert Rev Anticancer Ther 8:1053–1072PubMedCrossRefGoogle Scholar
  18. 18.
    Obeng EA, Carlson LM, Gutman DM et al (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107:4907–4916PubMedCrossRefGoogle Scholar
  19. 19.
    Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R (2008) Alkylating agents induce activation of NFkappaB in multiple myeloma cells. Leuk Res 32:1144–1147PubMedCrossRefGoogle Scholar
  20. 20.
    Hideshima T, Richardson P, Chauhan D et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076PubMedGoogle Scholar
  21. 21.
    Ma MH, Yang HH, Parker K et al (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144PubMedGoogle Scholar
  22. 22.
    Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedCrossRefGoogle Scholar
  23. 23.
    Catley L, Weisberg E, Kiziltepe T et al (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 108:3441–3449PubMedCrossRefGoogle Scholar
  24. 24.
    Pei XY, Dai Y, Grant S (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10:3839–3852PubMedCrossRefGoogle Scholar
  25. 25.
    Chauhan D, Velankar M, Brahmandam M et al (2007) A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene 26:2374–2380PubMedCrossRefGoogle Scholar
  26. 26.
    Gomez-Bougie P, Maiga S, Pellat-Deceunynck C et al (2006) The pan-Bcl-2 inhibitor GX15-O70 induces apoptosis in human myeloma cells by Noxa induction and strongly enhances melphalan, bortezomib or TRAIL-R1 antibody apoptotic effect [abstract]. Blood 108:991aGoogle Scholar
  27. 27.
    Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D (2007) The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109:4441–4449PubMedCrossRefGoogle Scholar
  28. 28.
    Liu FT, Agrawal SG, Gribben JG et al (2008) Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL. Blood 111:2797–2805PubMedCrossRefGoogle Scholar
  29. 29.
    Nencioni A, Wille L, Dal BG et al (2005) Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2- overexpressing cells. Clin Cancer Res 11:4259–4265PubMedCrossRefGoogle Scholar
  30. 30.
    Roue G, Perez-Galan P, Lopez-Guerra M et al (2007) Selective inhibition of IkappaB kinase sensitizes mantle cell lymphoma B cells to TRAIL by decreasing cellular FLIP level. J Immunol 178:1923–1930PubMedGoogle Scholar
  31. 31.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917PubMedCrossRefGoogle Scholar
  32. 32.
    Richardson PG, Mitsiades C, Ghobrial I, Anderson K (2006) Beyond single-agent bortezomib: combination regimens in relapsed multiple myeloma. Curr Opin Oncol 18:598–608PubMedCrossRefGoogle Scholar
  33. 33.
    Richardson PG, Hideshima T, Mitsiades C, Anderson KC (2007) The emerging role of novel therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw 5:149–162PubMedGoogle Scholar
  34. 34.
    Kahl BS, Peterson C, Blank J et al (2007) A feasibility study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma [abstract]. J Clin Oncol 25:456sCrossRefGoogle Scholar
  35. 35.
    Mounier N, Ribrag V, Haioun C et al (2007) Efficacy and toxicity of two schedules of R-CHOP plus bortezomib in front-line B lymphoma patients: a randomized phase II trial from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) [abstract]. J Clin Oncol 25:8010Google Scholar
  36. 36.
    Belch A, Kouroukis CT, Crump M et al (2007) A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol 18:116–121PubMedCrossRefGoogle Scholar
  37. 37.
    Drach J, Kaufmann H, Pichelmayer O et al (2007) Bortezomib, rituximab, and dexamethasone (BORID) as salvage treatment in relapsed/refractory mantle cell lymphoma: sustained disease control in patients achieving a complete remission [abstract]. Blood 110:760aGoogle Scholar
  38. 38.
    Fisher RI, Bernstein SH, Kahl BS et al (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867–4874PubMedCrossRefGoogle Scholar
  39. 39.
    Goy A, Bernstein S, Kahl B et al (2007) Durable responses with bortezomib in patients with relapsed or refractory mantle cell lymphoma (MCL): updated time-to-event analyses of the multicenter PINNACLE study [abstract]. Blood 110:45aCrossRefGoogle Scholar
  40. 40.
    O'Connor OA, Wright J, Moskowitz C et al (2005) Targeting the proteasome pathway with bortezomib in patients with mantle cell (MCL) and follicular lymphoma (FL) produces prolonged progression free survival among responding patients: results of a multicenter phase II experience [abstract]. Ann Oncol 16(Suppl 5):v66Google Scholar
  41. 41.
    Goy A, Younes A, McLaughlin P et al (2005) Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:667–675PubMedCrossRefGoogle Scholar
  42. 42.
    O'Connor OA, Wright J, Moskowitz C et al (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676–684PubMedCrossRefGoogle Scholar
  43. 43.
    Strauss SJ, Maharaj L, Hoare S et al (2006) Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity. J Clin Oncol 24:2105–2112PubMedCrossRefGoogle Scholar
  44. 44.
    De Vos S, Dakhil SR, McLaughlin P et al (2006) Phase 2 study of bortezomib weekly or twice weekly plus rituximab in patients with follicular (FL) or marginal zone (MZL) lymphoma: final results [abstract]. Blood 108:208aGoogle Scholar
  45. 45.
    Chen CI, Kouroukis CT, White D et al (2007) Bortezomib is active in patients with untreated or relapsed Waldenstrom’s macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1570–1575PubMedCrossRefGoogle Scholar
  46. 46.
    Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC et al (2005) Treatment of relapsed or refractory Waldenstrom’s macroglobulinemia with bortezomib. Haematologica 90:1655–1658PubMedGoogle Scholar
  47. 47.
    Treon SP, Hunter ZR, Matous J et al (2007) Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom’s macroglobulinemia: results of WMCTG Trial 03-248. Clin Cancer Res 13:3320–3325PubMedCrossRefGoogle Scholar
  48. 48.
    Treon SP, Ioakimidis L, Soumerai JD et al (2008) Primary therapy of Waldenstrom’s macroglobulinemia with bortezomib, dexamethasone and rituximab: results of WMCTG clinical trial 05-180 [abstract]. J Clin Oncol 26:8519Google Scholar
  49. 49.
    Kastritis E, Anagnostopoulos A, Roussou M et al (2007) Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 92:1351–1358PubMedCrossRefGoogle Scholar
  50. 50.
    Wechalekar AD, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD (2008) Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica 93:295–298PubMedCrossRefGoogle Scholar
  51. 51.
    Chauhan D, Li G, Shringarpure R et al (2003) Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 63:6174–6177PubMedGoogle Scholar
  52. 52.
    Hideshima T, Chauhan D, Ishitsuka K et al (2005) Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene 24:3121–3129PubMedCrossRefGoogle Scholar
  53. 53.
    McConkey DJ, Zhu K (2008) Mechanisms of proteasome inhibitor action and resistance in cancer. Drug Resist Updat 11:164–179PubMedCrossRefGoogle Scholar
  54. 54.
    Yang DT, Young KH, Kahl BS, Miyoshi S (2007) Bortezomib resistant constitutive NF-κB activation in mantle cell lymphoma [abstract]. Blood 110:1015aGoogle Scholar
  55. 55.
    Dreicer R, Petrylak D, Agus D, Webb I, Roth B (2007) Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Cancer Res 13:1208–1215PubMedCrossRefGoogle Scholar
  56. 56.
    Hainsworth JD, Meluch AA, Spigel DR et al (2007) Weekly docetaxel and bortezomib as first-line treatment for patients with hormone-refractory prostate cancer: a Minnie Pearl Cancer Research Network phase II trial. Clin Genitourin Cancer 5:278–283PubMedCrossRefGoogle Scholar
  57. 57.
    Fanucchi MP, Fossella FV, Belt R et al (2006) Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol 24:5025–5033PubMedCrossRefGoogle Scholar
  58. 58.
    Lara PN Jr, Koczywas M, Quinn DI et al (2006) Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. J Thorac Oncol 1:126–134PubMedCrossRefGoogle Scholar
  59. 59.
    Lynch TJ, Fenton DW, Hirsh V et al (2007) Randomized phase II study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 25:429sCrossRefGoogle Scholar
  60. 60.
    Ikezoe T, Yang Y, Saito T, Koeffler HP, Taguchi H (2004) Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells. Cancer Sci 95:271–275PubMedCrossRefGoogle Scholar
  61. 61.
    Williams S, Pettaway C, Song R et al (2003) Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther 2:835–843PubMedGoogle Scholar
  62. 62.
    Scagliotti G (2006) Proteasome inhibitors in lung cancer. Crit Rev Oncol Hematol 58: 177–189PubMedCrossRefGoogle Scholar
  63. 63.
    Schenkein DP (2005) Preclinical data with bortezomib in lung cancer. Clin Lung Cancer 7(Suppl 2):S49–S55PubMedCrossRefGoogle Scholar
  64. 64.
    Voortman J, Checinska A, Giaccone G (2007) The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells. Mol Cancer 6:73PubMedCrossRefGoogle Scholar
  65. 65.
    Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113–3120PubMedCrossRefGoogle Scholar
  66. 66.
    San Miguel JF, Richardson P, Sonneveld P et al (2005) Frequency, characteristics, and reversibility of peripheral neuropathy (PN) in the APEX trial [abstract]. Blood 106:111aGoogle Scholar
  67. 67.
    Csizmadia V, Raczynski A, Csizmadia E et al (2008) Effect of an experimental proteasome inhibitor on the cytoskeleton, cytosolic protein turnover, and induction in the neuronal cells in vitro. Neurotoxicology 29:232–243PubMedCrossRefGoogle Scholar
  68. 68.
    Silverman L, Csizmadia V, Kadambi VJ et al (2006) Model for proteasome inhibition associated peripheral neuropathy [abstract]. Toxicol Pathol 34:989Google Scholar
  69. 69.
    Silverman L, Csizmadia V, Brewer K, Simpson C, Alden C (2008) Proteasome inhibitor associated neuropathy is mechanism based [abstract]. Blood 112: Abstract 2646.Google Scholar
  70. 70.
    Moreau P, Coiteux V, Hulin C et al (2008) Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 93:1908–1911PubMedCrossRefGoogle Scholar
  71. 71.
    Dorsey BD, Iqbal M, Chatterjee S et al (2008) Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem 51:1068–1072PubMedCrossRefGoogle Scholar
  72. 72.
    Piva R, Ruggeri B, Williams M et al (2008) CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111:2765–2775PubMedCrossRefGoogle Scholar
  73. 73.
    Demo SD, Kirk CJ, Aujay MA et al (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67:6383–6391PubMedCrossRefGoogle Scholar
  74. 74.
    Feling RH, Buchanan GO, Mincer TJ et al (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42:355–357PubMedCrossRefGoogle Scholar
  75. 75.
    Tsueng G, Teisan S, Lam KS (2008) Defined salt formulations for the growth of Salinispora tropica strain NPS21184 and the production of salinosporamide A (NPI-0052) and related analogs. Appl Microbiol Biotechnol 78:827–832PubMedCrossRefGoogle Scholar
  76. 76.
    Groll M, Huber R, Potts BC (2006) Crystal structures of salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J Am Chem Soc 128:5136–5141PubMedCrossRefGoogle Scholar
  77. 77.
    Lightcap ES, McCormack TA, Pien CS et al (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46:673–683PubMedGoogle Scholar
  78. 78.
    Miller CP, Ban K, Dujka ME et al (2007) NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110:267–277PubMedCrossRefGoogle Scholar
  79. 79.
    Ruiz S, Krupnik Y, Keating M et al (2006) The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol Cancer Ther 5:1836–1843PubMedCrossRefGoogle Scholar
  80. 80.
    Roccaro AM, Leleu X, Sacco A et al (2008) Dual targeting of the proteasome regulates survival and homing in Waldenstrom’s macroglobulinemia. Blood 111:4752–4763PubMedCrossRefGoogle Scholar
  81. 81.
    Singh AV, Lloyd GK, Palladino MA, Chauhan D, Anderson KC (2008) Pharmacodynamic and efficacy studies of a novel proteasome inhibitor NPI-0052 in human plasmacytoma xenograft mouse model [abstract]. Blood 112: Abstract 3665Google Scholar
  82. 82.
    Muchamuel T, Aujay M, Bennett MK et al (2008) Preclinical pharmacology and in vitro characterization of PR-047, an oral inhibitor of the 20S proteasome [abstract]. Blood 112: Abstract 3671Google Scholar
  83. 83.
    Williamson MJ, Blank JL, Bruzzese FJ et al (2006) Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib. Mol Cancer Ther 5: 3052–3061PubMedCrossRefGoogle Scholar
  84. 84.
    Kisselev AF, Callard A, Goldberg AL (2006) Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J Biol Chem 281:8582–8590PubMedCrossRefGoogle Scholar
  85. 85.
    Arastu-Kapur S, Shenk K, Parlati F, Bennett MK (2008) Non-proteasomal targets of proteasome inhibitors bortezomib and carfilzomib [abstract]. Blood 112: Abstract 2657Google Scholar
  86. 86.
    Hideshima T, Mitsiades C, Akiyama M et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530–1534PubMedCrossRefGoogle Scholar
  87. 87.
    Kukreja A, Hutchinson A, Mazumder A et al (2007) Bortezomib disrupts tumour-dendritic cell interactions in myeloma and lymphoma: therapeutic implications. Br J Haematol 136:106–110PubMedCrossRefGoogle Scholar
  88. 88.
    Mitsiades N, Mitsiades CS, Poulaki V et al (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374–14379PubMedCrossRefGoogle Scholar
  89. 89.
    Strauss SJ, Higginbottom K, Juliger S et al (2007) The proteasome inhibitor bortezomib acts independently of p53 and induces cell death via apoptosis and mitotic catastrophe in B-cell lymphoma cell lines. Cancer Res 67:2783–2790PubMedCrossRefGoogle Scholar
  90. 90.
    Landowski TH, Megli CJ, Nullmeyer KD, Lynch RM, Dorr RT (2005) Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 65:3828–3836PubMedCrossRefGoogle Scholar
  91. 91.
    Chauhan D, Catley L, Li G et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 8:407–419PubMedCrossRefGoogle Scholar
  92. 92.
    Ahn KS, Sethi G, Chao TH et al (2007) Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF- kappaB regulated gene products. Blood 110:2286–2295PubMedCrossRefGoogle Scholar
  93. 93.
    Barral AM, Chao T-H, Kanabolooki S et al (2007) The proteasome inhibitor NPI-0052 reduces tumor growth and overcomes resistance of prostate cancer to rhTRAIL via inhibition of the NF-kß pathway [abstract]. Proc AACR 2007, Annual Meeting: Abstract 1465Google Scholar
  94. 94.
    Cusack JC Jr, Liu R, Xia L et al (2006) NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model. Clin Cancer Res 12:6758–6764PubMedCrossRefGoogle Scholar
  95. 95.
    Baritaki S, Suzuki E, Umezawa K et al (2008) Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells. J Immunol 180:6199–6210PubMedGoogle Scholar
  96. 96.
    Baritaki S, Chapman A, Wu K et al (2008) The novel proteasome inhibitor NPI-0052 induces the expression of Raf-1 kinase inhibitor protein (RKIP) in B-NHL via inhibition of the transcription repressor Snail: roles of Snail and RKIP in sensitization to TRAIL apoptosis [abstract]. Blood 112: Abstract 2611Google Scholar
  97. 97.
    Kuhn DJ, Chen Q, Voorhees PM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110:3281–3290PubMedCrossRefGoogle Scholar
  98. 98.
    Chao T-H, Barral AM, Lloyd KG et al (2008) The pharmacodynamic profile of NPI-0052 is cell-type specific [abstract]. Proc AACR 2008, Annual Meeting: Abstract 3257Google Scholar
  99. 99.
    Stapnes C, Doskeland AP, Hatfield K et al (2007) The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Br J Haematol 136:814–828PubMedCrossRefGoogle Scholar
  100. 100.
    Stewart AK, Sullivan D, Lonial S et al (2006) Pharmacokinetic (PK) and pharmacodynamics (PD) study of two doses of bortezomib (Btz) in patients with relapsed multiple myeloma (MM) [abstract]. Blood 108:1008aGoogle Scholar
  101. 101.
    Yang J, Fonseca F, Ho M et al (2006) Metabolism, disposition and pharmacokinetics of PR-171, a novel inhibitor of the 20S proteasome [abstract]. Blood 108: Abstract 5067Google Scholar
  102. 102.
    Kirk CJ, Jiang J, Muchamuel T et al (2008) The selective proteasome inhibitor carfilzomib is well tolerated in experimental animals with dose intensive administration [abstract]. Blood 112: Abstract 2765Google Scholar
  103. 103.
    Buglio D, Georgakis G, Yazbeck V et al (2007) A novel proteasome inhibitor, NPI-0052 is active in Hodgkin and mantle cell lymphoma cell lines [abstract]. Proc AACR 2007, Annual Meeting: Abstract 1454Google Scholar
  104. 104.
    Suzuki E, Palladino M, Cheng G, Bonavida B (2007) Sensitization of B-NHL resistant tumor cells overexpressing Bcl-xL to TRAIL-induced apoptosis by the novel proteasome inhibitor Salinosporamide A (NPI-0052) [abstract]. Proc AACR 2007, Annual Meeting: Abstract 1445Google Scholar
  105. 105.
    Sanchez E, Campbell RA, Steinberg JA et al (2008) The novel proteasome inhibitor CEP-18770 inhibits myeloma tumor growth in vitro and in vivo and enhances the anti-MM effects of melphalan [abstract]. Blood 112: Abstract 843Google Scholar
  106. 106.
    Huang X, Bailey K, Di Liberto M et al (2008) Induction of sustained early G1 arrest by selective inhibition of CDK4 and CDK6 primes myeloma cells for synergistic killing by proteasome inhibitors carfilzomib and PR-047 [abstract]. Blood 112: Abstract 3670Google Scholar
  107. 107.
    Paoluzzi L, Gonen M, Gardner JR et al (2008) Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 111:5350–5358PubMedCrossRefGoogle Scholar
  108. 108.
    Dajee M, Aujay M, Demo S et al (2008) The selective proteasome inhibitor carfilzomib in combination with chemotherapeutic agents improves anti-tumor response in solid tumor xenograft models [abstract]. Eur J Cancer 6:75Google Scholar
  109. 109.
    Chauhan D, Singh AV, Brahmandam M et al (2008) Combination of a novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vivo synergistic cytotoxicity in multiple myeloma [abstract]. Blood 112: Abstract 3662Google Scholar
  110. 110.
    Miller CP, Palladino M, Chandra J (2008) Overlapping functional activities of proteasome inhibitor, NPI-0052, and HDAC inhibitors contribute to synergistic cytotoxicity in leukemia cells [abstract]. Proc AACR 2008, Annual Meeting: Abstract 3255Google Scholar
  111. 111.
    Yazbeck VY, Georgakis GV, Li Y et al (2006) Inhibition of the pan-Bcl-2 family by the small molecule GX15-070 induces apoptosis in mantle cell lymphoma (MCL) cells and enhances the activity of two proteasome inhibitors (NPI-0052 and bortezomib), and doxorubicin chemotherapy [abstract]. Blood 108:716aGoogle Scholar
  112. 112.
    Sundi D, Fournier KF, Wray CJ, Marquis LM, McConkey DJ (2008) Combination treatment of pancreatic cancer cells with NPI-0052 and TRAIL activates heterogeneous apoptotic responses [abstract]. Proc ASCO 2008; Gastrointestinal Cancers Symposium: Abstract 183.Google Scholar
  113. 113.
    Wray C, Fournier KF, Sundi D, Marquis LM, McConkey DJ (2008) Combination proteasome- and histone deacetylase (HDAC) inhibitor treatment of pancreatic cancer [abstract]. Proc ASCO 2008; Gastrointestinal Cancers Symposium: Abstract 259Google Scholar
  114. 114.
    Cusack JC, Liu R, Xia L, Neuteboom S, Palladino M (2008) Salinosporamide A, a novel orally active proteasome inhibitor NPI-0052 enhances tumoricidal response to multidrug chemo- and molecular therapy regimens in a pancreatic cancer xenograft model [abstract]. Proc ASCO 2008; Gastrointestinal Cancers Symposium: Abstract 93Google Scholar
  115. 115.
    Chauhan D, Singh A, Brahmandam M et al (2008) Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111:1654–1664PubMedCrossRefGoogle Scholar
  116. 116.
    Richardson P, Hofmeister CC, Zimmerman TM et al (2008) Phase 1 clinical trial of NPI-0052, a novel proteasome inhibitor in patients with multiple myeloma [abstract]. Blood 112: Abstract 2770Google Scholar
  117. 117.
    Kurzrock R, Hamlin P, Gordon M et al (2008) NPI-0052 (a 2nd generation proteasome inhibitor) phase 1 study in patients with lymphoma and solid tumors [abstract]. Eur J Cancer 6:73–74Google Scholar
  118. 118.
    Townsend A, Padrik P, Mainwaring P et al (2008) Phase I clinical trial of the 2nd generation proteasome inhibitor NPI-0052 in patients with advanced malignancies with a CLL RP2D cohort [abstract]. Eur J Cancer 6:74Google Scholar
  119. 119.
    Orlowski RZ, Stewart K, Vallone M et al (2007) Safety and antitumor efficacy of the proteasome inhibitor carfilzomib (PR-171) dosed for five consecutive days in hematologic malignancies: phase 1 results [abstract]. Blood 110:127aGoogle Scholar
  120. 120.
    Alsina M, Trudel S, Vallone M et al (2007) Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies [abstract]. Blood 110:128aGoogle Scholar
  121. 121.
    Conner TM, Doan QD, Walters IB, LeBlanc AL, Beveridge RA (2008) An observational, retrospective analysis of retreatment with bortezomib for multiple myeloma. Clin Lymphoma Myeloma 8:140–145PubMedCrossRefGoogle Scholar
  122. 122.
    Sood R, Carloss H, Kerr R et al (2006) Retreatment with bortezomib alone or in combination for patients with multiple myeloma (MM) following an initial response to bortezomib: a phase IV, open-label trial [abstract]. Ann Oncol 17:ix205–ix206Google Scholar
  123. 123.
    Wolf J, Richardson PG, Schuster M et al (2008) Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol 6:755–760PubMedGoogle Scholar
  124. 124.
    Papadopoulos KP, Infante JR, Wong AF et al (2008) A phase I safety, pharmacokinetic and pharmacodynamic study of carfilzomib, a selective proteasome inhibitor, in subjects with advanced solid tumors [abstract]. Eur J Cancer 6:121Google Scholar
  125. 125.
    Vij R, Wang M, Orlowski R et al (2008) Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed myeloma (MM) [abstract]. Blood 112: Abstract 865Google Scholar
  126. 126.
    Jagannath S, Vij R, Stewart AK et al (2008) Initial results of PX-171-003, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM) [abstract]. Blood 112: Abstract 864Google Scholar
  127. 127.
    Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 5:596–613PubMedCrossRefGoogle Scholar
  128. 128.
    Adams J (2002) Development of the proteasome inhibitor PS-341. Oncologist 7:9–16PubMedCrossRefGoogle Scholar
  129. 129.
    Herrmann J, Lerman LO, Lerman A (2007) Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res 100:1276–1291PubMedCrossRefGoogle Scholar
  130. 130.
    Sun Y (2003) Targeting E3 ubiquitin ligases for cancer therapy. Cancer Biol Ther 2:623–629PubMedGoogle Scholar
  131. 131.
    Verma R, Peters NR, D'Onofrio M et al (2004) Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306:117–120PubMedCrossRefGoogle Scholar
  132. 132.
    Komada M (2008) Controlling receptor downregulation by ubiquitination and deubiquitination. Curr Drug Discov Technol 5:78–84PubMedCrossRefGoogle Scholar
  133. 133.
    Nicholson B, Marblestone JG, Butt TR, Mattern MR (2007) Deubiquitinating enzymes as novel anticancer targets. Future Oncol 3:191–199PubMedCrossRefGoogle Scholar
  134. 134.
    Chiba T, Tanaka K (2004) Cullin-based ubiquitin ligase and its control by NEDD8- conjugating system. Curr Protein Pept Sci 5:177–184PubMedCrossRefGoogle Scholar
  135. 135.
    Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K (2004) Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23:1985–1997PubMedCrossRefGoogle Scholar
  136. 136.
    Petroski MD, Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6:9–20PubMedCrossRefGoogle Scholar
  137. 137.
    Jones J, Wu K, Yang Y et al (2008) A targeted proteomic analysis of the ubiquitin-like modifier nedd8 and associated proteins. J Proteome Res 7:1274–1287PubMedCrossRefGoogle Scholar
  138. 138.
    Yen HC, Elledge SJ (2008) Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 322:923–929PubMedCrossRefGoogle Scholar
  139. 139.
    Smith PG, Milhollen M, Traore T et al (2007) Antitumor activity of MLN4924, a novel small molecule inhibitor of Nedd8-activating enzyme, in pre-clinical models of lymphoma [abstract]. Proceedings of Molecular Targets and Cancer Therapeutics 2007;331Google Scholar
  140. 140.
    Milhollen M, Narayanan U, Amidon B et al (2008) MLN4924, a potent and novel small molecule inhibitor of Nedd8 activating enzyme, induces DNA re-replication and apoptosis in cultured human tumor cells [abstract]. Eur J Cancer 6:113Google Scholar
  141. 141.
    Berger AJ, Yu J, Garnsey J et al (2008) Pharmacodynamic and efficacy relationship of MLN4924, a novel small molecule inhibitor of Nedd8-activating enzyme, in human xenograft tumors grown in immunocompromised mice [abstract]. Eur J Cancer 6:29Google Scholar
  142. 142.
    Milhollen M, Narayanan U, Duffy J et al (2008) MLN4924, a potent and novel small molecule inhibitor of Nedd8 activating enzyme, induces DNA re-replication and apoptosis in cultured human tumor cells [abstract]. Blood 112: Abstract 3621Google Scholar
  143. 143.
    Milhollen M, Narayanan U, Berger AJ et al (2008) MLN4924, a novel small molecule inhibitor of Nedd8-activating enzyme, demonstrates potent anti-tumor activity in diffuse large B-cell lymphoma [abstract]. Blood 112: Abstract 606Google Scholar
  144. 144.
    Kupperman E, Lee EC, Cao Y et al (2010) Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 70:1970–1980PubMedCrossRefGoogle Scholar
  145. 145.
    Zhou HJ, Aujay MA, Bennett MK et al (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52:3028–3038PubMedCrossRefGoogle Scholar
  146. 146.
    Roccaro AM, Sacco A, Aujay M et al (2010) Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood 115:4051–4060PubMedCrossRefGoogle Scholar
  147. 147.
    Muchamuel T, Basler M, Aujay MA et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15:781–787PubMedCrossRefGoogle Scholar
  148. 148.
    Kuhn DJ, Hunsucker SA, Chen Q et al (2009) Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113:4667–4676PubMedCrossRefGoogle Scholar
  149. 149.
    Rodler E, Infante JR, Shu L et al (2010) First-in-human, phase I dose-escalation study of investigational drug MLN9708, a second-generation proteasome inhibitor, in advanced nonhematologic malignancies [abstract]. J Clin Oncol 28(Suppl 15S):Abstract 3071Google Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Dixie-Lee Esseltine
    • 1
  • Larry Dick
    • 1
  • Erik Kupperman
    • 1
  • Mark Williamson
    • 1
  • Kenneth C. Anderson
    • 2
  1. 1.Millennium Pharmaceuticals IncCambridgeUSA
  2. 2.Jerome Lipper Center for Multiple MyelomaDana-Farber Cancer InstituteBostonUSA

Personalised recommendations