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Bortezomib and Osteoclasts and Osteoblasts

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Bortezomib in the Treatment of Multiple Myeloma

Part of the book series: Milestones in Drug Therapy ((MDT))

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Abstract

Bortezomib is the first-in-class proteasome antagonist approved for treatment of myeloma. It is active in newly diagnosed, relapsed, and refractory patients and is now being used as a platform for combinations with other new agents for myeloma. In addition to its anti-myeloma effect, bortezomib also targets the bone microenvironment and can inhibit osteoclast formation and stimulate osteoblast activity in patients with myeloma. Potentially, combination of bortezomib with other agents that stimulate bone formation or block bone resorption will further enhance the anti-myeloma effects of bortezomib and overcome the contribution of the tumor microenvironment to myeloma growth. In this chapter, we discuss the potential mechanisms responsible for bortezomib’s effects on osteoclast and osteoblast activity in myeloma.

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References

  1. Roodman GD (2009) Pathogenesis of myeloma bone disease. Leukemia 23(3):435–441

    Article  PubMed  CAS  Google Scholar 

  2. Saad AA, Sharma M, Higa GM (2009) Treatment of multiple myeloma in the targeted therapy era. Ann Pharmacother 43(2):329–338

    PubMed  CAS  Google Scholar 

  3. Mundy GR (1998) Myeloma bone disease. Eur J Cancer 34(2):246–251

    Article  PubMed  CAS  Google Scholar 

  4. Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE (1974) Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med 291(20):1041–1046

    Article  PubMed  CAS  Google Scholar 

  5. Diamond T, Levy S, Day P, Barbagallo S, Manoharan A, Kwan YK (1997) Biochemical, histomorphometric and densitometric changes in patients with multiple myeloma: effects of glucocorticoid therapy and disease activity. Br J Haematol 97(3):641–648

    Article  PubMed  CAS  Google Scholar 

  6. Berenson JR, Lipton A (1998) Use of bisphosphonates in patients with metastatic bone disease. Oncology (Williston Park) 12(11):1573–1579, discussion 1579–1581

    CAS  Google Scholar 

  7. Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaisse JM (2008) Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. Leuk Res 32(11):1661–1668

    Article  PubMed  CAS  Google Scholar 

  8. Uy GL, Goyal SD, Fisher NM, Oza AY, Tomasson MH, Stockerl-Goldstein K, DiPersio JF, Vij R (2009) Bortezomib administered pre-auto-SCT and as maintenance therapy post transplant for multiple myeloma: a single institution phase II study. Bone Marrow Transplant 43(10):793–800

    Article  PubMed  CAS  Google Scholar 

  9. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127(2):165–172

    Article  PubMed  CAS  Google Scholar 

  10. Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M et al (2008) Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol 143(4):537–540

    PubMed  Google Scholar 

  11. Esteve FR, Roodman GD (2007) Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 20(4):613–624

    Article  PubMed  CAS  Google Scholar 

  12. Calvani N, Silvestris F, Cafforio P, Dammacco F (2004) Osteoclast-like cell formation by circulating myeloma B lymphocytes: role of RANK-L. Leuk Lymphoma 45(2):377–380

    Article  PubMed  CAS  Google Scholar 

  13. Hjorth-Hansen H, Seifert MF, Borset M, Aarset H, Ostlie A, Sundan A, Waage A (1999) Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J Bone Miner Res 14(2):256–263

    Article  PubMed  CAS  Google Scholar 

  14. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, Spencer JA, Kimlinger T, Ghobrial JM, Jia X et al (2007) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109(7):2708–2717

    PubMed  CAS  Google Scholar 

  15. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7(8):585–598

    Article  PubMed  CAS  Google Scholar 

  16. Lentzsch S, Ehrlich LA, Roodman GD (2007) Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am 21(6):1035–1049, viii

    Article  PubMed  Google Scholar 

  17. Giuliani N, Morandi F, Tagliaferri S, Colla S, Bonomini S, Sammarelli G, Rizzoli V (2006) Interleukin-3 (IL-3) is overexpressed by T lymphocytes in multiple myeloma patients. Blood 107(2):841–842

    Article  PubMed  CAS  Google Scholar 

  18. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I et al (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96(7):3540–3545

    Article  PubMed  CAS  Google Scholar 

  19. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342

    Article  PubMed  CAS  Google Scholar 

  20. Matsuzaki K, Udagawa N, Takahashi N, Yamaguchi K, Yasuda H, Shima N, Morinaga T, Toyama Y, Yabe Y, Higashio K et al (1998) Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem Biophys Res Commun 246(1):199–204

    Article  PubMed  CAS  Google Scholar 

  21. Roodman GD (2007) Treatment strategies for bone disease. Bone Marrow Transplant 40(12):1139–1146

    Article  PubMed  CAS  Google Scholar 

  22. Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K, Shibata O, Udagawa N, Yasuda H, Suda T et al (1998) Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 246(2):337–341

    Article  PubMed  CAS  Google Scholar 

  23. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13(18):2412–2424

    Article  PubMed  CAS  Google Scholar 

  24. Sanz-Rodriguez F, Teixido J (2001) VLA-4-dependent myeloma cell adhesion. Leuk Lymphoma 41(3–4):239–245

    Article  PubMed  CAS  Google Scholar 

  25. Tai YT, Soydan E, Song W, Fulciniti M, Kim K, Hong F, Li XF, Burger P, Rumizen MJ, Nahar S et al (2009) CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells. Blood 113(18):4309–4318

    Article  PubMed  CAS  Google Scholar 

  26. Shi Y, Frost PJ, Hoang BQ, Benavides A, Sharma S, Gera JF, Lichtenstein AK (2008) IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res 68(24):10215–10222

    Article  PubMed  CAS  Google Scholar 

  27. Abe M, Hiura K, Ozaki S, Kido S, Matsumoto T (2009) Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production. J Bone Miner Metab 27(1):16–23

    Article  PubMed  CAS  Google Scholar 

  28. Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA, Dalton WS (2009) Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res 69(3):1009–1015

    Article  PubMed  CAS  Google Scholar 

  29. Perez LE, Parquet N, Shain K, Nimmanapalli R, Alsina M, Anasetti C, Dalton W (2008) Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. J Immunol 180(3):1545–1555

    PubMed  CAS  Google Scholar 

  30. Kumatori A, Tanaka K, Tamura T, Fujiwara T, Ichihara A, Tokunaga F, Onikura A, Iwanaga S (1990) cDNA cloning and sequencing of component C9 of proteasomes from rat hepatoma cells. FEBS Lett 264(2):279–282

    Article  PubMed  CAS  Google Scholar 

  31. Grisham MB, Palombella VJ, Elliott PJ, Conner EM, Brand S, Wong HL, Pien C, Mazzola LM, Destree A, Parent L et al (1999) Inhibition of NF-kappa B activation in vitro and in vivo: role of 26S proteasome. Methods Enzymol 300:345–363

    Article  PubMed  CAS  Google Scholar 

  32. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4(5): 349–360

    Article  PubMed  CAS  Google Scholar 

  33. 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(9):3828–3836

    Article  PubMed  CAS  Google Scholar 

  34. Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3(3):221–227

    Article  PubMed  CAS  Google Scholar 

  35. Hideshima T, Nakamura N, Chauhan D, Anderson KC (2001) Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20(42):5991–6000

    Article  PubMed  CAS  Google Scholar 

  36. Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, Podar K, Munshi NC, Richardson PG, Anderson KC (2003) Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene 22(52):8386–8393

    Article  PubMed  CAS  Google Scholar 

  37. Rajkumar SV, Kyle RA (2005) Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 80(10):1371–1382

    Article  PubMed  Google Scholar 

  38. von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M, Kaiser M, Jakob C, Sterz J, Kleeberg L et al (2007) Bortezomib inhibits human osteoclastogenesis. Leukemia 21(9):2025–2034

    Article  Google Scholar 

  39. Terpos E, Sezer O, Croucher P, Dimopoulos MA (2007) Myeloma bone disease and proteasome inhibition therapies. Blood 110(4):1098–1104

    Article  PubMed  CAS  Google Scholar 

  40. Pennisi A, Li X, Ling W, Khan S, Zangari M, Yaccoby S (2009) The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am J Hematol 84(1):6–14

    Article  PubMed  CAS  Google Scholar 

  41. Qiang YW, Hu B, Chen Y, Zhong Y, Shi B, Barlogie B, Shaughnessy JD Jr (2009) Bortezomib induces osteoblast differentiation via Wnt-independent activation of beta-catenin/TCF signaling. Blood 113(18):4319–4330

    Article  PubMed  CAS  Google Scholar 

  42. Silvestris F, Ciavarella S, De Matteo M, Tucci M, Dammacco F (2009) Bone-resorbing cells in multiple myeloma: osteoclasts, myeloma cell polykaryons, or both? Oncologist 14(3): 264–275

    Article  PubMed  CAS  Google Scholar 

  43. McConkey DJ (2009) Bortezomib paradigm shift in myeloma. Blood 114(5):931–932

    Article  PubMed  CAS  Google Scholar 

  44. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277(19):16639–16647

    Article  PubMed  CAS  Google Scholar 

  45. Hideshima T, Chauhan D, Ishitsuka K, Yasui H, Raje N, Kumar S, Podar K, Mitsiades C, Hideshima H, Bonham L et al (2005) Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene 24(19):3121–3129

    Article  PubMed  CAS  Google Scholar 

  46. Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, Cleveland JL, Giles FJ, McConkey DJ (2008) Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood 112(7): 2917–2926

    Article  PubMed  CAS  Google Scholar 

  47. Bennett EJ, Shaler TA, Woodman B, Ryu KY, Zaitseva TS, Becker CH, Bates GP, Schulman H, Kopito RR (2007) Global changes to the ubiquitin system in Huntington’s disease. Nature 448(7154):704–708

    Article  PubMed  CAS  Google Scholar 

  48. Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ, Kang SH, Yaccoby S, Najarian K, Richardson P et al (2005) Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol 131(1):71–73

    Article  PubMed  CAS  Google Scholar 

  49. Heider U, Kaiser M, Muller C, Jakob C, Zavrski I, Schulz CO, Fleissner C, Hecht M, Sezer O (2006) Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol 77(3):233–238

    Article  PubMed  CAS  Google Scholar 

  50. Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopoulos A, Pouli A, Katodritou E, Verrou E, Vervessou EC et al (2006) Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. Br J Haematol 135(5):688–692

    Article  PubMed  CAS  Google Scholar 

  51. Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M, Mancini C, Martella E, Ferrari L, Tabilio A et al (2007) The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 110(1):334–338

    Article  PubMed  CAS  Google Scholar 

  52. Edwards CM (2008) Wnt signaling: bone’s defense against myeloma. Blood 112(2):216–217

    Article  PubMed  CAS  Google Scholar 

  53. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J, Barlogie B, Shaughnessy JD Jr (2008) Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 112(1):196–207

    Article  PubMed  CAS  Google Scholar 

  54. Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S et al (2003) Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 111(11):1771–1782

    PubMed  CAS  Google Scholar 

  55. Terpos E (2008) Bortezomib directly inhibits osteoclast function in multiple myeloma: implications into the management of myeloma bone disease. Leuk Res 32(11):1646–1647

    Article  PubMed  Google Scholar 

  56. Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361(8):745–755

    Article  PubMed  CAS  Google Scholar 

  57. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361(8):756–765

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medicine/Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA

    Michal T. Krauze & G. David Roodman

  2. Veterans Affairs Pittsburgh Healthcare System, Research and Development, Department of Medicine/Hematology-Oncology, University of Pittsburgh School of Medicine, 151-U University Drive C, Rm. 2E113, Pittsburgh, PA, 15240, USA

    G. David Roodman

Authors
  1. Michal T. Krauze
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  2. G. David Roodman
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Correspondence to G. David Roodman .

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Editors and Affiliations

  1. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Irene M. Ghobrial

  2. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Paul G. Richardson

  3. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Kenneth C. Anderson

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Krauze, M.T., Roodman, G.D. (2011). Bortezomib and Osteoclasts and Osteoblasts. In: Ghobrial, I., Richardson, P., Anderson, K. (eds) Bortezomib in the Treatment of Multiple Myeloma. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-7643-8948-2_3

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