The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium.
Journal
Bone marrow transplantation
ISSN: 1476-5365
Titre abrégé: Bone Marrow Transplant
Pays: England
ID NLM: 8702459
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
18
03
2020
accepted:
04
05
2020
revised:
30
04
2020
pubmed:
15
5
2020
medline:
22
6
2021
entrez:
15
5
2020
Statut:
ppublish
Résumé
Multiple myeloma induction treatment includes proteasome inhibitors (PI) and immunomodulatory agents at present. The incidence of engraftment syndrome, a transplant complication potentially related to endothelium, has increased in the last years. Our aim was to investigate whether bortezomib (Velcade, V), thalidomide (T), and dexamethasone (D) affect the endothelium, and explore defibrotide (DF) as protective agent. Endothelial cells (ECs) in culture were exposed to the compounds separately or in combination, without (VTD) and with DF (VTD + DF). Changes in markers of: (i) inflammation (ICAM-1 expression and leukocyte adhesion), (ii) VWF production, (iii) cell permeability (VE-cadherin expression and cell monolayer integrity), and (iv) oxidative stress (ROS production and eNOS expression) were measured. ICAM-1 and VWF expression increased significantly in VTD but were similar to controls in VTD + DF. Separately, bortezomib was the main deleterious agent whereas dexamethasone showed no harmful effect. Leukocyte adhesion showed similar trends. VE-cadherin expression was lower in VTD and normalized in VTD + DF. EC permeability increased only with bortezomib. No changes were observed in oxidative stress markers. Our results demonstrate that bortezomib damages the endothelium, and DF prevents this effect. A better knowledge of the induction drugs impact will allow the design of measures to protect the endothelium.
Identifiants
pubmed: 32404979
doi: 10.1038/s41409-020-0947-9
pii: 10.1038/s41409-020-0947-9
doi:
Substances chimiques
Bortezomib
69G8BD63PP
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2270-2278Subventions
Organisme : Jazz Pharmaceuticals (Jazz Pharmaceuticals plc)
ID : IST-16-10355
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PIE15/00027
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : DTS16/00133
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI19/00888
Organisme : Generalitat de Catalunya (Government of Catalonia)
ID : 2017-SGR675
Références
Li Z, Rubinstein SM, Thota R, Savani M, Brissot E, Shaw BE, et al. Immune-mediated complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2016;22:1368–75.
Koniarczyk HL, Ferraro C, Miceli T. Hematopoietic stem cell transplantation for multiple myeloma. Semin Oncol Nurs. 2017;33:265–78.
pubmed: 28729120
Gerecke C, Fuhrmann S, Strifler S, Schmidt-Hieber M, Einsele H, Knop S. Medicine: the diagnosis and treatment of multiple myeloma. Dtsch Arztebl Int. 2016;113:470–6.
pubmed: 27476706
pmcid: 4973001
Cavo M, Terpos E, Bargay J, Einsele H, Cavet J, Greil R, et al. The multiple myeloma treatment landscape: international guideline recommendations and clinical practice in Europe. Expert Rev Hematol. 2018;11:219–37.
pubmed: 29415570
Cornell RF, Hari P, Zhang M-J, Zhong X, Thompson J, Fenske TS, et al. Divergent effects of novel immunomodulatory agents and cyclophosphamide on the risk of engraftment syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma. Biol Blood Marrow Transpl. 2013;19:1368–73.
Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transpl. 2011;46:1495–502.
DeLeve LD, Wang X, Kanel GC, Ito Y, Bethea NW, McCuskey MK, et al. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology. 2003;38:900–8.
pubmed: 14512877
DeLeve LD, Wang X, Tsai J, Kanel G, Strasberg S, Tokes ZA. Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition. Gastroenterology. 2003;125:882–90.
pubmed: 12949732
DeLeve LD, Ito Y, Bethea NW, McCuskey MK, Wang X, McCuskey RS. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome. Am J Physiol Liver Physiol. 2003;284:G1045–52.
Nürnberger W, Willers R, Burdach S, Göbel U. Risk factors for capillary leakage syndrome after bone marrow transplantation. Ann Hematol. 1997;74:221–4.
pubmed: 9200994
Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002;166:641–5.
pubmed: 12204858
George JN. ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. Curr Hematol Rep. 2005;4:167–9.
pubmed: 15865866
George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44:294–304.
pubmed: 14962323
Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Martine C, et al. Endothelial dysfunction after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation. Biol Blood Marrow Transplant. 2010;16:985–93.
pubmed: 20167280
Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M. Post-transplant complications engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant. 2003;31:393–7.
pubmed: 12634731
Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8.
pubmed: 11436099
Katzel JA, Mazumder A, Jagannath S, Vesole DH. Engraftment syndrome after hematopoietic stem cell transplantation in multiple myeloma. Clin Lymphoma Myeloma. 2006;7:151.
pubmed: 17026829
Gao Y, Ma G, Liu S, Teng Y, Wang Y, Su Y. Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro. Thromb Res. 2015;135:1154–9.
pubmed: 25840743
Na W, Shin JY, Lee JY, Jeong S, Kim WS, Yune TY, et al. Dexamethasone suppresses JMJD3 gene activation via a putative negative glucocorticoid response element and maintains integrity of tight junctions in brain microvascular endothelial cells. J Cereb Blood Flow Metab. 2017;37:3695–708.
pubmed: 28338398
pmcid: 5718327
Palomo M, Diaz-Ricart M, Carreras E. Endothelial dysfunction in hematopoietic cell transplantation. Clin Hematol Int. 2019;1:45.
Akil A, Zhang Q, Mumaw CL, Raiker N, Yu J, Velez de Mendizabal N, et al. Biomarkers for diagnosis and prognosis of sinusoidal obstruction syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015;21:1739–45.
pubmed: 26172478
pmcid: 4568166
Mir E, Palomo M, Rovira M, Pereira A, Escolar G, Penack O, et al. Endothelial damage is aggravated in acute GvHD and could predict its development. Bone Marrow Transplant. 2017;52:1317–25.
pubmed: 28650450
Martinez-Sanchez J, Hamelmann H, Palomo M, Mir E, Moreno-Castaño AB, Torramade S, et al. Acute graft-vs.-host disease-associated endothelial activation in vitro is prevented by defibrotide. Front Immunol. 2019;10:2339.
pubmed: 31649666
pmcid: 6794443
Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Escolar G, et al. The release of soluble factors contributing to endothelial activation and damage after hematopoietic stem cell transplantation is not limited to the allogeneic setting and involves several pathogenic mechanisms. Biol Blood Marrow Transplant. 2009;15:537–46.
pubmed: 19361745
Gutiérrez-García G, Rovira M, Magnano L, Rosiñol L, Bataller A, Suárez-Lledó M, et al. Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018;53:1541–7.
pubmed: 29706650
Eissner G, Multhoff G, Gerbitz A, Kirchner S, Bauer S, Haffner S, et al. Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood. 2002;100:334–40.
pubmed: 12070045
Palomo M, Vera M, Martin S, Torramadé-Moix S, Martinez-Sanchez J, Moreno AB, et al. Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide. J Cell Mol Med. 2019;24:1713–23.
pubmed: 31782253
pmcid: 6991634
Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010;16:1005–17.
pubmed: 20167278
pmcid: 2956581
Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589–96.
pubmed: 22791289
Carmona A, Díaz-Ricart M, Palomo M, Molina P, Pino M, Rovira M, et al. Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus–sirolimus on endothelial cells: protective effect of defibrotide. Biol Blood Marrow Transplant. 2013;19:1439–45.
pubmed: 23845694
Malard F, Harousseau JL, Mohty M. Anti-tumour treatment multiple myeloma treatment at relapse after autologous stem cell transplantation: a practical analysis. Cancer Treat Rev. 2017;52:41–7.
pubmed: 27888768
Oyama Y, Cohen B, Traynor A, Brush M, Rodriguez J, Burt RK. Case report engraftment syndrome: a common cause for rash and fever following autologous hematopoietic stem cell transplantation for multiple sclerosis. Bone Marrow Transplant. 2002;29:81–5.
pubmed: 11840150
Carreras E, Fernádez-Avilés F, Silva L, Guerrero M, Fernández De Larrea C, Martínez C, et al. Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center. Bone Marrow Transplant. 2010;45:1417–22.
pubmed: 20062097
Falci SGM, Lima TC, Martins CC, Dos Santos CRR, Pinheiro MLP. Preemptive effect of dexamethasone in third-molar surgery: A Meta-analysis. Anesth Prog. 2017;64:136–43.
pubmed: 28858550
pmcid: 5579814
Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36:561–84.
pubmed: 29196868
Kubiczkova L, Pour L, Sedlarikova L, Hajek R, Sevcikova S. Proteasome inhibitors—molecular basis and current perspectives in multiple myeloma. J Cell Mol Med. 2014;18:947–61.
pubmed: 24712303
pmcid: 4508135
Ludwig A, Fechner M, Wilck N, Meiners S, Grimbo N, Baumann G, et al. Potent anti-inflammatory effects of low-dose proteasome inhibition in the vascular system. J Mol Med. 2009;87:793–802.
pubmed: 19399470
Vestweber D. VE-cadherin: The major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol. 2008;28:223–32.
pubmed: 18162609
Li W, Fu J, Zhang S, Zhao J, Xie N, Cai G. The proteasome inhibitor bortezomib induces testicular toxicity by upregulation of oxidative stress, AMP-activated protein kinase (AMPK) activation and deregulation of germ cell development in adult murine testis. Toxicol Appl Pharm. 2015;285:98–109.
Sahni A, Thomasson ED, Shah R, Sahni SK. Bortezomib effects on human microvascular endothelium in vitro. Pharmacology. 2016;98:272–8.
pubmed: 27578289
Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54:683–7.
pubmed: 22966948
Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med. 2001;344:1951–2.
pubmed: 11419443
Rafiee P, Stein DJ, Nelson VM, Otterson MF, Shaker R, Binion DG. Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC). Am J Physiol Gastrointest Liver Physiol. 2010;298:G167–76.
pubmed: 19926820
Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–23.
pubmed: 16236742
Swan D, Rocci A, Bradbury C, Thachil J. Venous thromboembolism in multiple myeloma—choice of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol. 2018;183:538–56.
pubmed: 30450656
Pescador R, Capuzzi L, Mantovani M, Fulgenzi A, Ferrero ME. Defibrotide: properties and clinical use of an old/new drug. Vasc Pharm. 2013;59:1–10.
Palomo M, Diaz-Ricart M, Rovira M, Escolar G, Carreras E. Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:497–506.
pubmed: 21126597
Palomo M, Mir E, Rovira M, Escolar G, Carreras E, Diaz-Ricart M. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood. 2016;127:1719–27.
pubmed: 26755708
pmcid: 4817313