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Proteasome Inhibition: a New Strategy in Cancer Treatment

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Abstract

The ubiquitin proteasome pathway is a highly conservedintracellular pathway for the degradation of proteins. Many of theshort-lived regulatory proteins which govern cell division, growth,activation, signaling and transcription are substrates that aretemporally degraded by the proteasome. In recent years, new andselective inhibitors of the proteasome have been employed in cellculture systems to examine the anti-tumor potential of theseagents. This review covers the chemistry of selected proteasomeinhibitors, possible mechanisms of action in cell culture and thein vivo examination of proteasome inhibitors in murine andhuman xenograft tumor models in mice. One inhibitor, PS-341, hasrecently entered Phase I clinical trials in cancer patients withadvanced disease to further test the potential of this approach.

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References

  1. Peters JM, Harris JR, Finley D, editors: Ubiquitin and the Biology of the Cell. Plenum Press NY, Chapters 1–6, 1998

    Google Scholar 

  2. Ciechanover A: The ubiquitin-proteasome pathway: on protein death and cell life. EMBO Journal 24: 7151–7160, 1998

    Google Scholar 

  3. Lee DH, Goldberg AL: Proteasome inhibitors: valuable new tools for cell biologists. Trend Cell Biol 8: 397–403, 1998

    Google Scholar 

  4. Spataro V, Norbury C, Harris AL: The ubiquitin-proteasome pathway in cancer. Brit J Cancer 77: 448–455, 1998

    Google Scholar 

  5. Hershko A: Roles of ubiquitin-mediated proteolysis in cell cycle control. Curr Op Cell Biol 9: 788–799, 1997

    Google Scholar 

  6. Wilk S, Pereira M, Yu B: Probing the specificity of the bovine pituitary multicatalytic proteinase complex by inhibitors, activators, and by chemical modification. Biomed Biochim Acta 50: 471–478, 1991

    Google Scholar 

  7. Orlowski M, Cardozo C, Michaud C: Evidence for the presence of five distinct proteolytic components in the pituitary multicatalytic protemase complex. Properties of two components cleaving bonds on the carboxyl side of branched chain and small neutral amino acids. Biochemistry 32: 1563–1572, 1993

    Google Scholar 

  8. An B, Goldfarb RH, Siman R, Dou QP: Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed but not normal human fibroblasts. Cell Death Differ 12: 1062–1075, 1998

    Google Scholar 

  9. Lum RT, Nelson MG, Joly A, Horsma AG, Lee G, Meyer SM, Wick MM, Schow SR: Selective Inhibition of the Chymotrypsin-like Activity of the 20S Proteasome by 5-methoxy-1-indanone dipeptide benzamides. Bioorg Med Chem Let 8: 209–214, 1998

    Google Scholar 

  10. lqbal M, Chatterjee S, Kauer JC, Mallamo JP, Messina PA, Reiboldt A, Siman R: Potent alpha-ketocarbonyl and boronic ester derived inhibitors of proteasome. BioorgMed Chem Let 6: 287–290, 1996

    Google Scholar 

  11. Adams J, Behnke M, Chen S, Cruickshank AA, Dick LR, Grenier L, Klunder JM, Ma YT, Planiondon L, Stein RL: Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Let 8: 333–338, 1998

    Google Scholar 

  12. Lowe J, Stock D, Jap R, Zwickl P, Baumeister W, Huber R: Crystal structure of the 20S proteasome from the archaeon T. acidophiluin at 3.4 A resolution. Science 268: 533–539, 1995

    Google Scholar 

  13. Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL: Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268: 726–731, 1995

    Google Scholar 

  14. Dick LR, Cruickshank AA, Grenier L, Melandri FD, Nunes SL, Stein RL: Mechanistic studies on the inactivation of the proteasome by lactacystin in cultured cells. J Biol Chem 271: 7273–7276, 1996

    Google Scholar 

  15. McCormack T, Baumeister W, Grenier, Moomaw C, Plamondon L, Pramanik, B, Slaughter C, Soucy F, Stein RL, Zuhl F, Dick L: Active site-directed inhibitors of rhodococcus 20S proteasome. J Biol Chem 272: 26103–26109, 1997

    Google Scholar 

  16. Bogyo M, McMaster JS, Gaczynska M, Tortorella D, Goldberg AL, Ploegh H: Covalent modification of the active site threonine of proteasomal B subunits and the Escherichia coli homologue Hs IV by a new class of inhibitors. Proc Nat Ac Sci 94: 6629–6634, 1997

    Google Scholar 

  17. Groettrup M, Schmidtke G: Selective proteasome inhibitors: Modulators of antigen presentation? DDT 4: 63–70 1999

    Google Scholar 

  18. Crews CM, Sin N, Meng L: Natural products as molecular probes of angiogenesis. Book of Abstracts, 215th ACS National Meeting, Dallas, Mar 29-Apr 2, 1998, MEDI 208

  19. Figueiredo-Pereira ME, Chen WE, Li J, Johdo 0: The antitumor drug aclacinomycin A which inhibits the degradation of ubiquitinated proteins, shows selectivity for the chymotrypsinlike activity of the bovine pituitary 20S proteasome. J Biol Chem 271: 16455–16459, 1996

    Google Scholar 

  20. Meyer S, Kohler NG, Joy A: Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-κB activation. FEBS Letters 413: 354–358, 1997

    Google Scholar 

  21. Wang X, Omura S, Szweda LI, Yang Y, Berard J, Seminaro J, Wu J: Rapamycin inhibits proteasome activator expression and proteasome activity. Eur J Immunol 27: 2781–2786, 1997

    Google Scholar 

  22. Andre P, Groettrup M, Klenerman P, de Giuli R, Booth BL Jr, Cerundolo V, Bonneville M, Jotereau F, Zinkemagel RM, Lotteau V: An inhibitor of HIV-I protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Nat Ac Sci 95: 13120–13124, 1998

    Google Scholar 

  23. King RW, Deshaies RJ, Peters JM, Kirschner MW: How proteolysis drives the cell cycle. Science 274: 1652–1659, 1996

    Google Scholar 

  24. Blagosklonny MV, Wu GS, Omura S, EI-Deiry WS: Proteasome-dependent regulation of p2lWAF1=CIP1 expression. Biochem Biophys Res Com 227: 564–569, 1996

    Google Scholar 

  25. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M: Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269: 682–685, 1995

    Google Scholar 

  26. Machiels BM, Henfling MER, Gerards WLH, Broers JLV, Bloemendal H, Ramaekers FCS, Schutte B: Detailed analysis of cell cycle kinetics upon proteasome inhibition. Cytometry 28: 243–252, 1997

    Google Scholar 

  27. Maki CG, Huibregtse JM, Howley PM: In vivo ubiquitination and proteasome-mediated degradation of p53. Cancer Research 56: 2649–2654, 1996

    Google Scholar 

  28. Smith EJ, Leone G, Nevins JR: Distinct mechanisms control the mechanism of the Rb-related p107 and p130 proteins during cell growth. Cell Growth Differentiation 9: 297–303, 1998

    Google Scholar 

  29. Baldin V, Cans C, Knibiehler M, Ducommun B: Phosphorylation of human cdc25B phosphatase by cdk1-cyclin A triggers its proteasome-dependent degradation. J Biol Chem 272: 32731–32734, 1997

    Google Scholar 

  30. Gross-Mesilaty S, Hargrove JL, Ciechanover A: Degradation of tyrosine aminotransferase (TAT) via the ubiquitin-proteasome pathway. FEBS Let 405: 175–180, 1997

    Google Scholar 

  31. Hoffman EK, Wilcox HM, Scott RW, Siman R: Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. J Neurol Sci 139: 15–20, 1996

    Google Scholar 

  32. Latres E, Chiaur DS, Pagano M: The human F box protein B-Trcp associates with the Cul1/Skp1 complex and regulates the stability of B-catenin. Oncogene 18: 849–854, 1999

    Google Scholar 

  33. Tsurumi C, Ishida N, Tamura T, Kakizuka A, Nishida E, Okumura E, Kishimoto T, Inagaki M, Okazaki K, Sagata N, Ichihara A, Tanaka K: Degradation of c-Fos by the 26S pro119 teasome is accelerated by c-Jun and multiple protein kinases. Mol Cell Biol 15: 5682–5687, 1995

    Google Scholar 

  34. Gross-Mesilaty S, Reinstein E, Bercovich B, Tobias KE, Schwartz AL, Kahana C, Ciechanover A: Basal and human papillornavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Nat Ac Sci 95: 8058–8063, 1998

    Google Scholar 

  35. Maniatis T: A ubiquitin ligase complex essential for the NF-kappa-B, Wnt/Wingless, and hedgehog signaling pathways. Genes Dev 5: 505–510, 1999

    Google Scholar 

  36. Hochstrasser M: Ubiquitin-dependent protein degradation. Annu Rev Genet 30: 405–439, 1996

    Google Scholar 

  37. Hoyt MA: Eliminating all obstacles: regulated proteolysis in the eukaryotic cell cycle. Cell 91: 149–151, 1997

    Google Scholar 

  38. Sherr CJ: Cancer cell cycles. Science 274: 1672–1677, 1996

    Google Scholar 

  39. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM: The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75: 495–505, 1993

    Google Scholar 

  40. Chandra J, Niemer I, Gilbreath J, Kliche KO, Andreeff M, Freireich EJ, Keating M, McConkey DJ: Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood 92: 4220–4229, 1998

    Google Scholar 

  41. Drexler HC: Activation of the cell death program by inhibition of proteasome, function. Proc Nat Ac Sci 94: 855–860, 1997

    Google Scholar 

  42. Shinohara K, Tomioka M, Nakano H, Tone S, Ito H, Kawashima S: Apoptosis induction resulting from proteasome inhibition. Biochem J 317 (Pt2): 385–388, 1996

    Google Scholar 

  43. Meriin AB, Gabai VL, Yaglorn J, Shiffin VI, Sherman MY: Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis. J Biol Chem 273: 6373–6379, 1998

    Google Scholar 

  44. Imajoh-Ohmi S, Kawaguchi T, Sugiyama S, Tanaka K, Omura S, Kikuchi H: Lactacystin, a specific inhibitor of the proteasome, induces apoptosis in human monoblast U937 cells. Biochem Biophys Res Commun 217: 1070–1077, 1995

    Google Scholar 

  45. Lopes UG, Erhardt P, Yao R, Cooper GM: p53-dependent induction of apoptosis by proteasome inhibitors. J Biol Chem 272: 12893–12896, 1997

    Google Scholar 

  46. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ: Proteasome inhibitors: A novel class of potent and effective anti-tumor agents. In press: Cancer Res 59: 2615–2622, 1999. See alsoWebsite: dtp.nci.nih.gov search NSC #681239

    Google Scholar 

  47. Boyd MR, Paull D: Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Devel Res 34: 91–109, 1995

    Google Scholar 

  48. Grimm LM, Goldberg AL, Poirier GG, Schwartz LM, Osborne BA: Proteasomes play an essential role in thymocyte apoptosis. EMBO J 15: 3835–3844, 1996

    Google Scholar 

  49. Sadoul R, Fernandez PA, Quiquerez AL, Martinou 1, Maki M, Schroter M, Becherer JD, Irmler M, Tschopp J, Martinou JC: Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons. EMBO J 15: 3845–3852, 1996

    Google Scholar 

  50. Dietrich C, Bartsch T, Schanz F, Oesch F, Wieser RJ: p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. Proc Nat Ac Sci 93: 10815–10819, 1996

    Google Scholar 

  51. Glas R, Bogyo M, McMaster JS, Gaczynska M, Ploegh HL: A proteolytic system that compensates for loss of proteasome function. Nature 392: 618–622, 1998

    Google Scholar 

  52. Delic J, Masdehors P, Omura S, Cosset JM, Dumont J, Binet JL, Magdelenat H: The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo-and radioresistant human chronic lymphocytic leukemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer 77: 1103–1107, 1998

    Google Scholar 

  53. Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV: Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. Cancer Res 58: 4342–4348, 1998

    Google Scholar 

  54. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T: The ubiquitin-proteasome pathway is required for processing the NF-kappa-B1 precursor protein and the activation of NF-kappa-B. Cell 78: 773–785, 1994

    Google Scholar 

  55. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T: Signalinduced site-specific phosphorylation targets I-kappa-B-alpha to the ubiquitin-proteasome pathway. Genes Devel 9: 1586–1597, 1995

    Google Scholar 

  56. Palombella VJ, Conner EM, Fuseler JW, Destree A, Davis JM, Laroux FS, Wolf RE, Huang J, Brand S, Elliott PJ, Lazarus D, McCormack T, Parent L, Stein R, Adams J, Grisham MB: Role of the proteasome and NF-kappa-B in streptococcal cell wall-induced polyarthritis. Proc Nat Ac Sci 95: 15671–15676, 1998

    Google Scholar 

  57. Bellas RE, FitzGerald MJ, Fausto N, Sonenshein GE: Inhibition of NF-kappa-13 activity induces apoptosis in murine hepatocytes. Am J Pathol 151: 891–896, 1997

    Google Scholar 

  58. Baldwin AS Jr: The NF-kappa-B and I-kappa-B proteins: new discoveries and insights. Ann Rev Immunol 14: 649–683, 1996

    Google Scholar 

  59. Thanos D, Maniatis T: NF-kappa-B: A lesson in family values. Cell 80: 529–532, 1995

    Google Scholar 

  60. Grilli M, Chiu JJ, Lenardo MJ: NF-kappa-B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol 143: 1–62, 1993

    Google Scholar 

  61. Baeuerle PA, Baltimore D: NF-kappa-B: Ten years after. Cell 87: 13–20, 1996

    Google Scholar 

  62. Beg AA, Baltimore D: An essential role for NF-kappa-B in preventing TNF-alpha-induced cell death. Science 274: 782–784, 1996

    Google Scholar 

  63. Van Antwerp DJ, Martin SJ, Kafri T, Green Dr, Verma IM: Suppression of TNF-alpha-induced apoptosis by NF-kappa-B. Science 274: 787–789, 1996

    Google Scholar 

  64. Wang CY, Mayo MW, Baldwin AS Jr: TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappa-B. Science 274: 784–787, 1996

    Google Scholar 

  65. Mayo MW, Wang CY, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ, Baldwin AS Jr: Requirement of NF-kappa-B activation to suppress p-53-independent apoptosis induced by oncogenic Ras. Science 278: 1812–1815, 1997

    Google Scholar 

  66. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW: Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappa-B control. Proc Nat Ac Sci 94: 10057–10062, 1997

    Google Scholar 

  67. You M, Ku PT, Hrdlickova R, Bose FIR Jr: ch-IAP1 a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-Rel oncoprotein. Mol Cell Biol 17: 7328–7341, 1997

    Google Scholar 

  68. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr: NF-kappa-B antiapoptosis: induction of TRAF1 and TRAF2 and c-lAP1 and c-IAP2 to suppress caspase-8 activation. Science 281: 1680–1683, 1998

    Google Scholar 

  69. Wu MX, Ao Z, Prasad KV, Wu R, Schlossman SF: IEX-1L, an apoptosis inhibitor involved in NF-kappa-B-mediated cell survival. Science 281: 998–1001, 1998

    Google Scholar 

  70. Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C: The prosurvival bcl-2 homologue bfl-1/A1 is a direct transcriptional target of NF-kappa-B that blocks TNF-alpha induced apoptosis. Genes Devel 13: 382–387, 1999

    Google Scholar 

  71. Grumont RJ, Rourke IJ, Gerondakis S: Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Devel 13: 400–411, 1999

    Google Scholar 

  72. Wang CY, Cusack JC, Liu I, Baldwin AS Jr: Control of inducible chemoresistance: enhanced anti-tumor therapy via increased apoptosis through inhibition of NF-κB. Nat Med 5: 412–417, 1999

    Google Scholar 

  73. Jeremias I, Kupatt C, Baumann B, Herr I, Wirth T, Debatin KM: Inhibition of nuclear factor kappa-B activation attenuates apoptosis resistance in lymphoid cells. Blood 91: 4624–4631, 1998

    Google Scholar 

  74. Mikulski SM, Viera A, Deptala A, Darzynkiewicz Z: Enhanced in vitro cytoxicity and cytostasis of the combination of onconase with a proteasome inhibitor. Int J Oncol 13: 633–644, 1998

    Google Scholar 

  75. Lin ZP, Boller YC, Amer SM, Russell RL, Pacelli KA, Patierno SR, Kennedy KA: Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG 132: Involvement of NF-kappa-B activation in drug resistance. Cancer Res 58: 3059–3065, 1998

    Google Scholar 

  76. Stoklosa T, Wojcik C, Golab J, Giermasz A, Wilk S: Inhibition of proteasome, apoptosis, and sensitization to tumor necrosis factor alpha: do they always go together? Br J Cancer 79: 375–376, 1999

    Google Scholar 

  77. Bentires-Alj M, Hellin AC, Ameyar M, Chouaib S, Merville MP, Bours V: Stable inhibition of nuclear factor kappa-B in cancer cells does not increase sensitivity to cytotoxic drugs. Cancer Res 59: 811–815, 1999

    Google Scholar 

  78. Dabholkar M, Reed E: Cisplatin. Cancer Chemother Biol Resp Modif 16: 88–110, 1996

    Google Scholar 

  79. Mimnaugh EG, Yunmbam MK, Li Q, Bonvini P, Hwang SG, Trepel J, Reed E, Neckers L: Proteasome inhibitors block repair of cisplatin-DNA adducts in human ovarian carcinoma cells. Cancer Res, In press

  80. Adams JM, Cory S: The bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326, 1998

    Google Scholar 

  81. Herrmann JL, Beharn AW, Sarkiss M, Chiao PJ, Rands MT, Bruckheimer EM, Brisbay S, McDonnell TJ: Bcl-2 suppresses apoptosis resulting from disruption of the NF-kappa-B survival pathway. Exp Cell Res 237: 101–109, 1997

    Google Scholar 

  82. He H, Qi XM, Grossmann J, Distelhorst CW: c-Fos degradation by the proteasome. An early, bcl-2-regulated step in apoptosis. J Biol Chem 273: 25015–25019, 1998

    Google Scholar 

  83. de Moissac D, Mustapha S, Greenberg AH, Kirshenbaum LA: Bcl-2 activates the transcription factor NF-kappa-B through the degradation of the cytoplasmic inhibitor I-kappa-B-alpha. J Biol Chem 273: 23946–23951, 1998

    Google Scholar 

  84. Herrmann JL, Briones F Jr, Brisbay S, Logothetis CJ, Mc-Donnell TJ: Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of fimctional bcl-2 and p53. Oncogene 17: 2889–2899, 1998

    Google Scholar 

  85. Zetter BR: Adhesion molecules in tumor metastasis. Semin Cancer Biol 4: 219–229, 1993

    Google Scholar 

  86. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T: Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa-B and cytokine-inducible enhancers. FASEB J 9: 899–909, 1995

    Google Scholar 

  87. Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T: The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity 2: 493–506, 1995

    Google Scholar 

  88. Teicher BA, Ara G, Herbst I, Palombella VJ, Adams J: The Proteasome inhibitor PS-341 in cancer therapy. In press: J Clin Cancer Res 1999

  89. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376: 517–519, 1995

    Google Scholar 

  90. Folkman J: Angiogenesis and Angiogenesis Inhibition: An Overview, EXS 79: 1–8, 1997

    Google Scholar 

  91. Oikawa T, Sasaki T, Nakamura M, Shimamura M, Tanahashi N, Omura S, Tanaka K: The proteasome is involved in angiogenesis. Biochem Biophys Res Commun 246: 243–248, 1998

    Google Scholar 

  92. Wang X, Luo H, Chen H, Duguid W, Wu J: Role of proteasomes in T cell activation and proliferation. J Immunol 160: 788–801, 1998

    Google Scholar 

  93. Vives-Pi M, Vargas F, James RFL, Trowsdale J, Costa M, Sospedra M, Somoza N, Obiols G, Tampe R, Pujol-Borelli R: Proteasome subunits, low-molecular-mass polypeptides 2 and 7 are hyperexpressed by target cells in autoimmune thyroid disease but not in insulin-dependent diabetes mellitus: implications for autoirnmunity. Tiss Ant 50: 153–163, 1997

    Google Scholar 

  94. Hoffman EK, Wilcox HM, Scott RW, Siman R: Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. J Neurol Sci 139: 15–20, 1996

    Google Scholar 

  95. Feist E, Dorner T, Kuckelkorn U, Schmidtke G, Micheel B, Hiepe F, Burmester GR, Kloetzel PM: Proteasome a-type subunit C9 is a primary target of autoantibodies in sera of patients with myositis and systemic lupus erythematosus. J Exp Med 10: 1313–1318, 1996

    Google Scholar 

  96. Elliott PJ, Pien CS, McCormack TA, Chapman ID, Adams J: Proteasome inhibition: a novel mechanism to combat asthma. In press: J All Clin Immunol 1999

  97. Vanderlugt CL, Rahbe SM, Elliott PJ, Dal Canto MC, Miller SD: Treatment of established relapsing experimental autoirnmune encephalomyelitis with the proteasome inhibitor PS-519. In press: J Neuro Imunnol

  98. Campbell B, Adams J, Shin YK, Lefer AM: Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. J Mol Cell Card 31: 467–476, 1999

    Google Scholar 

  99. Phillips JB, Williams A, Dave JR, Elliott PJ, Tortella FC: PS-519, A novel proteasome inhibitor, reduces infarction in a rat model of ischemia/reperfusion brain injury. J Neurosci Abst 24: 215, #86.11, 1998

    Google Scholar 

  100. Phillips JB, Williams A, Elliott PJ, Tortella FC: A novel proteasome inhibitor, PS-519, shows neuroprotective efficacy in a rat model of transient focal ischemia. FASEB J 13: A1099 #817.3, 1999

    Google Scholar 

  101. Proteasome Inhibitor, PS-341, IND #56,515, submission to the FDA, July 1998

  102. Shibatani T, Nazir M, Ward W: Alteration of rat liver 20S proteasome activities by age and food restriction. J Geront 51A: B316–322, 1996

    Google Scholar 

  103. Desai SD, Liu LF, Vazquez-Abad D, D'Arpa P: Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 272: 24159–24164, 1997

    Google Scholar 

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    Julian Adams, Vito J. Palombella & Peter J. Elliott

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Adams, J., Palombella, V.J. & Elliott, P.J. Proteasome Inhibition: a New Strategy in Cancer Treatment. Invest New Drugs 18, 109–121 (2000). https://doi.org/10.1023/A:1006321828515

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