Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia : An In Silico Approach
Lozano, Maria L. (Hospital General Universitario Morales Meseguer (Múrcia))
Segú-Vergés, Cristina (Anaxomics Biotech SL)
Coma, Mireia (Anaxomics Biotech SL)
Alvarez-Román, María Teresa (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
González-Porras, José Ramón (Hospital Universitario de Salamanca)
Gutiérrez, Laura (Universidad de Oviedo)
Valcárcel, David (Vall d'Hebron Institut d'Oncologia)
Butta, Nora (Hospital Universitario La Paz (Madrid))
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94. 92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Eltrombopag ; Primary immune thrombocytopenia ; Immunomodulation ; In silico ; Systems biology ; Mathematical modelling ; Artificial intelligence
Publicado en:	International journal of molecular sciences, Vol. 22 (june 2021) , ISSN 1422-0067

DOI: 10.3390/ijms22136907
PMID: 34199099

16 p, 1.9 MB

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