Promises and pitfalls in erythopoietin-mediated tissue protection: Are nonerythropoietic derivatives a way forward?

Journal of Investigative Medicine

Volumn 59, Issue 7, 2011, Pages 1073-1082

  Hand, Carla Cerami ^a   Brines, Michael ^b  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

^b Warren Pharmaceuticals Inc   (United States)

Author keywords

Apoptosis; Cytokines; Cytoprotection; Inflammation; Innate immune response

Indexed keywords

ANTIANEMIC AGENT; ARA 290; CYTOKINE; ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR; JANUS KINASE 1; JANUS KINASE 2; MITOGEN ACTIVATED PROTEIN KINASE; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; PEPTIDE; RECOMBINANT ERYTHROPOIETIN; STAT3 PROTEIN; STAT5A PROTEIN; TISSUE PROTECTIVE RECEPTOR; UNCLASSIFIED DRUG;

ADJUVANT THERAPY; ANEMIA; ANGIOGENESIS; APOPTOSIS; BLOOD BRAIN BARRIER; BLOOD CLOTTING; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; BRAIN MALARIA; CANCER PATIENT; CELL PROTECTION; CONFERENCE PAPER; CRITICALLY ILL PATIENT; DIABETIC PATIENT; DISEASE COURSE; DRUG FATALITY; DRUG MEGADOSE; DRUG RECEPTOR BINDING; DRUG SAFETY; ENDOTHELIAL PROGENITOR CELL; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; FRIEDREICH ATAXIA; HEART FAILURE; HEART INFARCTION; HEART PROTECTION; HEMATOPOIESIS; HUMAN; HYPOXIC ISCHEMIC ENCEPHALOPATHY; IMMUNE RESPONSE; INFLAMMATION; INNATE IMMUNITY; KIDNEY ISCHEMIA; META ANALYSIS (TOPIC); MORTALITY; NEOVASCULARIZATION (PATHOLOGY); NEUROLOGIC DISEASE; NEUROPROTECTION; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); POSTOPERATIVE CARE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPERFUSION INJURY; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SPINAL CORD INJURY; STEM CELL; STROKE; SURGICAL PATIENT; THROMBOEMBOLISM; THROMBOPHLEBITIS; TISSUE INJURY; TRAUMATIC BRAIN INJURY; TREATMENT OUTCOME; TUMOR CELL; TUMOR GROWTH; WOUND HEALING;

EID: 80054993756     PISSN: 17088267     EISSN: 17088267     Source Type: Journal    
DOI: 10.2310/JIM.0b013e3181ed30bf     Document Type: Conference Paper

References (118)

1. Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Med Biol. 2003;228:1-14. (Pubitemid 36077622)
2. Anagnostou A, Lee ES, Kessimian N, et al. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA. 1990;87:5978-5982.
3. Masuda S, Nagao M, Takahata K, et al. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J. Biol. Chem. 1993;268: 11208-11216. (Pubitemid 23162313)
4. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA. 2004;101:14907-14912. (Pubitemid 39410773)
5. Sautina L, Sautin Y, Beem E, et al. Induction of nitric oxide by erythropoietin is mediated by the {beta} common receptor and requires interaction with VEGF receptor 2. Blood. 2009;115:896-905.
6. Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Int Med. 2008;264:405-432.
7. Brines M, Cerami A. Discovering erythropoietin's extra-hematopoietic functions: biology and clinical promise. Kidney Int. 2006;70:246-250. (Pubitemid 44086573)
8. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA. 2000;97:10526-10531.
9. Arcasoy M. The non-haematopoietic biological effects of erythropoietin. Br J Haematol. 2008;141:14-31. (Pubitemid 351347536)
10. Minnerup J, Heidrich J, Rogalewski A, et al. The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke. 2009;40:3113-3120.
11. Jerndal M, Forsberg K, Sena E, et al. A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab. 2010;30(5):961-968.
12. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495-505. (Pubitemid 36337492)
13. Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647-e656.
14. Zechariah A, Elali A, Hermann D. Combination of tissue-plasminogen activator with erythropoietin induces blood-brain barrier permeability, extracellular matrix disaggregation, and DNA fragmentation after focal cerebral ischemia in mice. Stroke. 2010;41:1008-1012.
15. Cherian L, Goodman JC, Robertson C. Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmcol Exp Thera. 2007;322:789-794. (Pubitemid 47105820)
16. Zhang Y, Xiong Y, Mahmood A, et al. Therapeutic effects of erythropoietin on histological and functional outcomes following traumatic brain injury in rats are independent of hematocrit. Brain Res. 2009;1294:153-164.
17. Lu D, Mahmood A, Qu C, et al. Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma. 2005;22:1011-1017. (Pubitemid 41362067)
18. Celik M, Gökmen N, Erbayraktar S, et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA. 2002;99: 2258-2263. (Pubitemid 34169048)
19. Gorio A, Madaschi L, Di Stefano B, et al. Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci USA. 2005;102: 16379-16384. (Pubitemid 41688922)
20. Grasso G, Sfacteria A, Erbayraktar S, et al. Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative. J Neurosurg. 2006;4:310-318. (Pubitemid 47325461)
21. King VR, Averill SA, Hewazy D, et al. Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat. Eur J Neurosci. 2007;26:90-100. (Pubitemid 47035440)
22. Vitellaro-Zuccarello L, Mazzetti S, Madaschi L, et al. Chronic erythropoietin-mediated effects on the expression of astrocyte markers in a rat model of contusive spinal cord injury. Neuroscience. 2008;151:452-466.
23. Yoo JY, Won YJ, Lee JH, et al. Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. J Neurosci Res. 2009;87:150-163.
24. Kaiser K, Texier A, Ferrandiz J, et al. Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J Infect Dis. 2006;193:987-995.
25. Wiese L, Hempel C, Penkowa M, et al. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malaria J. 2008;7:3.
26. Casals-Pascual C, Idro R, Gicheru N, et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc Natl Acad Sci USA. 2008;105:2634-2639. (Pubitemid 351520565)
27. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124:e218-e226.
28. Brown M, Eichorst D, Lala-Black B, et al. Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. Pediatrics. 2009;124:e681-e687.
29. Agnello D, Bigini P, Villa P, et al. Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res. 2002;952:128-134. (Pubitemid 35279495)
30. Savino C, Pedotti R, Baggi F, et al. Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. J Neuroimmunol. 2006;172:27-37. (Pubitemid 43279681)
31. Yuan R, Maeda Y, Li W, et al. Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS ONE. 2008;3:e1924.
32. Grasso G. Neuroprotective effect of recombinant human erythropoietin in experimental subarachnoid hemorrhage. J Neurosurg Sci. 2001;45:7-14. (Pubitemid 32694787)
33. Grasso G, Buemi M, Alafaci C, et al. Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci USA. 2002;99:5627-5631. (Pubitemid 34411600)
34. Miskowiak K, Favaron E, Hafizi S, et al. Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study. Psychopharm. 2009;207:133-142.
35. Miskowiak K, O'Sullivan U, Harmer CJ. Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action. Biol Psychiatry. 2007;62:1244-1250. (Pubitemid 350060886)
36. Ehrenreich H, Hinze-Selch D, Stawicki S, et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry. 2006;12:206-220.
37. Lauria G, Campanella A, Filippini G, et al. Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability. Amyotroph Lateral Scler. 2009;10:410-415.
38. Ehrenreich H, Fischer B, Norra C, et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain. 2007;130:2577-2588. (Pubitemid 47511714)
39. Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA. 2003;100:4802-4806. (Pubitemid 36457809)
40. Baker J. Erythropoietin mimics ischemic preconditioning. Vasc Pharmacol. 2005;42:233-241. (Pubitemid 40726326)
41. Cai Z, Manalo D, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108:79-85. (Pubitemid 36859024)
42. Cai Z, Semenza G. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation. 2004;109: 2050-2053. (Pubitemid 38620210)
43. Rafiee P, Shi Y, Su J, et al. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol. 2005;100:187-197. (Pubitemid 41348809)
44. Abdelrahman M, Sharples EJ, McDonald MC, et al. Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock. 2004;22:63-69. (Pubitemid 40228212)
45. Kim KH, Oudit GY, Backx PH. Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. J Pharmacol Exp Ther. 2008; 324:160-169. (Pubitemid 350294149)
46. Tramontano A, Muniyappa R, Black A, et al. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun. 2003;308: 990-994. (Pubitemid 36976556)
47. Wright G, Hanlon P, Amin K, et al. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J. 2004;18:1031-1033. (Pubitemid 39561515)
48. Depping R, Kawakami K, Ocker H, et al. Expression of the erythropoietin receptor in human heart. J Thorac Cardiovasc Surg. 2005;130:877-878.
49. van der Meer P, Groenveld HF, Januzzi JL, et al. Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart. 2009;95:1309-1314.
50. Mancini D, Katz S, Lang C, et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;107:294-299. (Pubitemid 36135227)
51. Binbrek AS, Rao NS, Al Khaja N, et al. Erythropoietin to augment myocardial salvage induced by coronary thrombolysis in patients with ST segment elevation acute myocardial infarction. Am J Cardiol. 2009;104:1035-1040.
52. Ferrario M, Arbustini E, Massa M, et al. High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol. 2009. [Epub ahead of print].
53. Parsa C, Matsumoto A, Kim J, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest. 2003;112: 999-1007. (Pubitemid 38056315)
54. Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2005;102: 2046-2051. (Pubitemid 40262009)
55. Tabira T, Konishi Y, Gallyas F. Neurotrophic effect of hematopoietic cytokines on cholinergic and other neurons in vitro. Int J Develop. 1995;13:241-252.
56. Yamaji R, Okada T, Moriya M, et al. Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. Eur J Biochem. 1996;239:494-500. (Pubitemid 26246558)
57. Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA. 2001;98:4044-4049. (Pubitemid 32249895)
58. Konishi Y, Chui DH, Hirose H, et al. Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res. 1993;609:29-35. (Pubitemid 23136796)
59. Viviani B, Bartesaghi S, Corsini E, et al. Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem. 2005;93: 412-421. (Pubitemid 40547498)
60. Bernaudin M, Marti HH, Roussel S, et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab. 1999;19:643-651. (Pubitemid 30161216)
61. Siren AL, Knerlich F, Poser W, et al. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta neuropathologica. 2001;101:271-276. (Pubitemid 32219761)
62. Chin K, Yu X, Beleslin-Cokic B, et al. Production and processing of erythropoietin receptor transcripts in brain. Mol Brain Res. 2000;81:29-42.
63. Santhanam AV, Katusic ZS. Erythropoietin and cerebral vascular protection: role of nitric oxide. Acta Pharmacol Sin. 2006;27: 1389-1394. (Pubitemid 44630304)
64. Gunnarson E, Song Y, Kowalewski J, et al. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci USA. 2009;106:1602-1607.
65. Wojchowski DM, Gregory RC, Miller CP, et al. Signal transduction in the erythropoietin receptor system. Exper Cell Res. 1999;253: 143-156.
66. Wang L, Zhang ZG, Gregg SR, et al. The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem. 2007;282:32462-32470. (Pubitemid 350106478)
67. Byts N, Samoylenko A, Fasshauer T, et al. Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ. 2008;15:783-792. (Pubitemid 351405083)
68. Um M, Gross A, Lodish H. A Bclassical[ homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5-and pheochromocytoma PC-12 cells. Cellular signalling. 2007;19: 634-645. (Pubitemid 46107815)
69. Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032.
70. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373: 1532-1542.
71. Haiden N, Cardona F, Schwindt J, et al. Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity. Thromb Haemost. 2005;93:118-123. (Pubitemid 40124265)
72. Kato S, Amano H, Ito Y, et al. Effect of erythropoietin on angiogenesis with the increased adhesion of platelets to the microvessels in the hind-limb ischemia model in mice. J Pharmacol Sci. 2010;112:167-175.
73. Kirkeby A, Torup L, Bochsen L, et al. High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO). Thromb Haemost. 2008;99:720-728. (Pubitemid 351694228)
74. Stasko J, Galajda P, Ivanková J, et al. Soluble P-selectin during a single hemodialysis session in patients with chronic renal failure and erythropoietin treatment. Clinical and applied thrombosis/hemostasis. 2007;13:410-415. (Pubitemid 350114513)
75. Stohlawetz PJ, Dzirlo L, Hergovich N, et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983-2989. (Pubitemid 30235913)
76. Wolf RF, Gilmore LS, Friese P, et al. Erythropoietin potentiates thrombus development in a canine arterio-venous shunt model. Thromb Haemost. 1997;77:1020-1024. (Pubitemid 27239133)
77. Wolf RF, Peng J, Friese P, et al. Erythropoietin administration increases production and reactivity of platelets in dogs. Thromb Haemost. 1997;78:1505-1509. (Pubitemid 27519398)
78. Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or Darbepoetin for patients with cancerYmeta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009; (3):CD007303.
79. Diskin C, Stokes T, Dansby L, et al. Beyond anemia: the clinical impact of the physiologic effects of erythropoietin. Sem Dialysis. 2008;21:447-454.
80. Fandrey J, Dicato M. Examining the involvement of erythropoiesis- stimulating agents in tumor proliferation (erythropoietin receptors, receptor binding, signal transduction), angiogenesis, and venous thromboembolic events. The Oncologist. 2009;14(suppl 1):34-42.
81. Napolitano L, Fabian T, Kelly K, et al. Improved survival of critically ill trauma patients treated with recombinant human erythropoietin. J Trauma. 2008;65:285-297.
82. Kertesz N, Wu J, Chen THP, et al. The role of erythropoietin in regulating angiogenesis. Dev Biol. 2004;276:101-110. (Pubitemid 39452849)
83. Ribatti D, Presta M, Vacca A, et al. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood. 1999;93:2627-2636. (Pubitemid 29181195)
84. Haroon Z, Amin K, Jiang X, et al. A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol. 2003;163:993-1000. (Pubitemid 37040135)
85. Masuda S, Kobayashi T, Chikuma M, et al. The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am J Physiol. 2000;278:E1038-E1044. (Pubitemid 30439141)
86. Yasuda Y, Musha T, Tanaka H, et al. Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer. 2001;84:836-843. (Pubitemid 32275660)
87. Hardee M, Cao Y, Fu P, et al. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE. 2007;2:e549.
88. Yasuda Y, Masuda S, Chikuma M, et al. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem. 1998;273:25381-25387. (Pubitemid 28443305)
89. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001;61:3561-3565. (Pubitemid 32694960)
90. Acs G, Zhang P, McGrath C, et al. Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol. 2003;162:1789-1806. (Pubitemid 36613038)
91. Fu P, Jiang X, Arcasoy M. Constitutively active erythropoietin receptor expression in breast cancer cells promotes cellular proliferation and migration through a MAP-kinase dependent pathway. Biochem Biophys Res Commun. 2009;379:696-701.
92. Kumar S, Yu H, Fong D, et al. Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells. Melanoma Res. 2006;16:275-283. (Pubitemid 44090171)
93. Mohyeldin A, Lu H, Dalgard C, et al. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia. 2005;7:537-543. (Pubitemid 40791872)
94. Paragh G, Kumar SM, Rakosy Z, et al. RNA interference-mediated inhibition of erythropoietin receptor expression suppresses tumor growth and invasiveness in A2780 human ovarian carcinoma cells. Am J Pathol. 2009:174(4):1504-1514.
95. Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kid Internat. 2000;58:647-657. (Pubitemid 30620014)
96. Liu WM, Powles T, Shamash J, et al. Effect of haemopoietic growth factors on cancer cell lines and their role in chemosensitivity. Oncogene. 2004;23:981-990. (Pubitemid 38250944)
97. Rosti V, Pedrazzoli P, Ponchio L, et al. Effect of recombinant human erythropoietin on hematopoietic and non-hematopoietic malignant cell growth in vitro. Haematologica. 1993;78:208-212. (Pubitemid 23323068)
98. Elliott S, Busse L, Bass M, et al. Anti-EPO receptor antibodies do not predict EPO receptor expression. Blood. 2006;107:1892-1895. (Pubitemid 43289368)
99. Sinclair AM, Rogers N, Busse L, et al. Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer. 2008;98:1059-1067. (Pubitemid 351399799)
100. Swift S, Ellison A, Kassner P, et al. Absence of functional EpoR expression in human tumor cell lines. Blood. 2010:115(21):4254-4263.
101. Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA. 2003;100:6741-6746. (Pubitemid 36666650)
102. Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305:239-242. (Pubitemid 38886736)
103. Boissel JP, Lee WR, Presnell SR, et al. Erythropoietin structure-function relationships. Mutant proteins that test a model of tertiary structure. J Biol Chem. 1993;268:15983-15993. (Pubitemid 23222105)
104. Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nature Struct Biol. 1998;5:861-866. (Pubitemid 28467406)
105. Elliott S, Lorenzini T, Chang D, et al. Mapping of the active site of recombinant human erythropoietin. Blood. 1997;89:493-502. (Pubitemid 27051684)
106. Wen D, Boissel JP, Showers M, et al. Erythropoietin structure-function relationships. Identification of functionally important domains. J. Biol. Chem. 1994;269:22839-22846.
107. Coleman TR, Westenfelder C, Togel FE, et al. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA. 2006;103:5965-5970.
108. Erbayraktar S, de Lanerolle N, de Lotbiniere A, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med. 2006;12:74-80. (Pubitemid 44454094)
109. Fantacci M, Bianciardi P, Caretti A, et al. Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia. Proc Natl Acad Sci USA. 2006;103:17531-17536. (Pubitemid 44789003)
110. Mennini T, De Paola M, Bigini P, et al. Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Mol Med. 2006;12:153-160. (Pubitemid 44646344)
111. Fu Z-Q, Shao Q-L, Shen J-L, et al. Effect of carbamylated erythropoietin on major histocompatibility complex expression and neural differentiation of human neural stem cells. J Neuroimmunol. 2010;221:15-24.
112. Imamura R, Okumi M, Isaka Y, et al. Carbamylated erythropoietin improves angiogenesis and protects the kidneys from ischemia-reperfusion injury. Cell Transplant. 2008;17:135-141. (Pubitemid 351551389)
113. Mahmood A, Lu D, Qu C, et al. Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg. 2007;107:392-397. (Pubitemid 47219384)
114. Wang Y, Zhang ZG, Rhodes K, et al. Post-ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. British journal of pharmacology. 2007;151:1377-1384. (Pubitemid 47255890)
115. Xu X, Cao Z, Cao B, et al. Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery. 2009;146:506-514.
116. Jubinsky PT, Krijanovski OI, Nathan DG, et al. The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood. 1997;90:1867-1873. (Pubitemid 27377296)
117. Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci USA. 2008;105:10925-10930.
118. Sakanaka M, Wen TC, Matsuda S, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA. 1998;95:4635-4640. (Pubitemid 28207965)