Abstract
Bortezomib, a proteasome inhibitor, has shown immunosuppressive activity in animal models of GVHD. In this study, we evaluated the effects of Bortezomib on the survival of monocytes, a major circulating source of DCs. PBMCs or purified CD14+ monocytes were cultured for 24 h with Bortezomib (0.1–100 ng/ml). Apoptosis was demonstrated on the basis of detection of phosphatydilserine. Bortezomib induced a significant dose-dependent depletion (P=0.008) of monocytes in PBMC preparations, with <1% CD14+ cells remaining at doses ⩾5 ng/ml. Moreover, Bortezomib decreased the survival of purified monocytes within 24 h (P=0.004) (n=6). Monocyte loss was due to apoptosis (effective dose 50%, ED50, 1–10 ng/ml). In addition, both immature and mature monocyte-derived DC underwent apoptosis following exposure to Bortezomib. Kinetic experiments showed that apoptosis increased at 16 h through 24 h of culture. However, short term (4 h) incubation with Bortezomib irreversibly committed monocytes to undergo apoptosis at 24, 72 and 144 h. Instead, Bortezomib induced no apoptosis of purified CD19+ B, CD3+ T lymphocytes and CD34+ progenitor cells (ED50 >50 ng/ml). The inhibitory effect of Bortezomib on professional APCs, such as monocytes and DCs, suggests its possible use in GVHD prophylaxis.
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References
Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME et al. Approval summary for Bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 2004; 10: 3954–3964.
Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24: 4867–4874.
Richardson P . Clinical update: proteasome inhibitors in hematologic malignancies. Cancer Treatment Rev 2003; 29 (S1): 33–39.
Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001; 82: 110–122.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS341. Blood 2003; 101: 1530–1534.
Orlowski RZ, Small GW, Shi YY . Evidence that inhibition of p44/42 mitogen-activated protein kinase signalling is a factor in preteasome inhibitor-mediated apoptosis. J Biol Chem 2002; 277: 27864–27871.
Mortenson MM, Schlieman MG, Virudachalam S, Lara PN, Gandara DG, Davies AM et al. Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer. Lung Cancer 2005; 49: 163–170.
Blanco B, Perez-Simon JA, Sanchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 2006; 107: 3575–3583.
Sun K, Welniak LA, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Liu H, Barao I et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. PNAS 2004; 101: 8120–8125.
Sun K, Wilkins DEC, Anver MR, Sayers TJ, Panoskaltsis-Mortari A, Blazar BR et al. Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood 2005; 106: 3293–3299.
Nencioni A, Schwarzenberg K, Brauer KM, Schmidt SM, Ballestrero A, Grunebach F et al. The proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood 2006; 108: 551–558.
Nencioni A, Garuti A, Schwarzenberg K, Cirmena G, Dal Bello G, Rocco I et al. Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells. Eur J Immunol 2006; 36: 681–689.
Subklewe M, Sebelin-Wulf K, Beier C, Lietz A, Mathas S, Dorken B et al. Dendritic cell maturation stage determines susceptibility to the proteasome inhibitor bortezomib. Hum Immunol 2007; 68: 147–155.
Naujokat C, Berges C, Hoh A, Wieczorek H, Fuchs D, Ovens J et al. Proteasomal chymotrypsin-like peptidase activity is required for essential functions of human monocyte-derived dendritic cells. Immunology 2006; 120: 120–132.
Straube C, Wehner R, Wendisch M, Bornhauser M, Bachmann M, Rieber EP et al. Bortezomib significantly impairs the immunomodulatory capacity of human myeloid blood dendritic cells. Leukemia 2007; 21: 1464–1471.
Blanco B, Palucka AK, Gill M, Pascual V, Banchereau J . Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 2001; 294: 1540–1543.
Sambo P, Jannino L, Candela M, Salvi A, Donini M, Dusi S et al. Monocytes of patients with systemic sclerosis (scleroderma) spontaneously release in vitro increased amounts of superoxide anion. J Investiv Dermatol 1999; 112: 78–84.
Shlomchik WC . Antigen presentation in graft-vs-host disease. Exp Hematol 2003; 31: 1187–1197.
Arpinati M, Chirumbolo G, Saunthararajah Y, Stanzani M, Bonifazi F, Bandini G et al. Higher numbers of blood CD14+ cells before starting conditioning regimen correlate with greater risk of acute graft-versus-host disease in allogeneic stem cell transplantation from related donors. Biol Blood Marrow Transplant. 2007; 13: 228–234.
Arpinati M, Terragna C, Chirumbolo G, Rizzi S, Urbini B, Re F et al. Human CD34(+) blood cells induce T-cell unresponsiveness to specific alloantigens only under costimulatory blockade. Exp Hematol 2003; 31: 31–38.
Yu Q, Chow EM, Wong H, Gu J, Mandelboim O, Gray-Owen SD et al. CEACAM1 (CD66a) promotes human monocyte survival via a phosphatidylinositol 3-kinase and AKT-dependent pathway. J Biol Chem 2006; 281: 39179–39193.
Fraser JK, Lill MC, Figlin RA . The biology of the cytokine sequence cascade. Semin Oncol 1996; 23 (Suppl 4): 2–8.
Curti A, Isidori A, Ferri E, Terragna C, Neyroz P, Cellini C et al. Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy. Leuk Lymphoma 2004; 45: 1419–1428.
Schwartz R, Davidson T . Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology 2004; 18: 14–21.
Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA . Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 1999; 11: 753–761.
Kukreja A, Hutchinson A, Mazumder A, Vesole D, Angitapalli R, Jagannath S et al. Bortezomib disrupts tumour-dendritic cell interactions in myeloma and lymphoma: therapeutic implications. Br J Haematol 2006; 136: 106–110.
Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D . The proteasome inhibitor bortezomib induces apoptosis in mantle cell lymphoma through generation of ROS species and noxa activation independent of p53 status. Blood 2006; 107: 257–264.
Marriott HM, Bingle CD, Read RC, Braley KE, Kroemer G, Hellewell PG et al. Dynamic changes in mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J Clin Invest 2005; 115: 359–368.
Woltman AM, van der Kooij SW, Coffer PJ, Offringa R, Daha MR, van Kooten C . Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. 2003; 101: 1439–1445.
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis and overcomes drug resistance in human multiple myeloma cells. Cancer Reasearch 2001; 61: 3071–3076.
Ling YH, Liebes L, Jiang JD, Holland JF, Elliott PJ, Adams J et al. Mechanisms of proteasome inhibitor PS-341-induced G2 −M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res 2003; 9: 1145–1154.
Arpinati M, Chirumbolo G, Baccarani M, Rondelli D . Increased expression of CD86 and CXCR4 in CD14+ cells in peripheral blood and bone marrow of patients with chronic GVHD. Transplantation 2008; 85: 1826–1832.
Mateos-Mazon J, Perez-Simon JA, Lopez O, Hernandez E, Etxebarria J, San Miguel JF . Use of Bortezomib in the management of chronic graft-versus-host disese among multiple myeloma patiets relapsing after allogenec transplantation. Haematologica 2007; 92: 1295–1296.
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This research was partly supported by MURST (Rome, Italy) and Bologna AIL (Bologna, Italy).
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Arpinati, M., Chirumbolo, G., Nicolini, B. et al. Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade). Bone Marrow Transplant 43, 253–259 (2009). https://doi.org/10.1038/bmt.2008.312
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DOI: https://doi.org/10.1038/bmt.2008.312
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