Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach
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 pat...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6907 |
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| author | Maria L. Lozano Cristina Segú-Vergés Mireia Coma María T. Álvarez-Roman José R. González-Porras Laura Gutiérrez David Valcárcel Nora Butta |
| author_facet | Maria L. Lozano Cristina Segú-Vergés Mireia Coma María T. Álvarez-Roman José R. González-Porras Laura Gutiérrez David Valcárcel Nora Butta |
| author_sort | Maria L. Lozano |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T10:01:05Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:01:05Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d8f1b533f1844d279e8663762337fe122023-11-22T01:57:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213690710.3390/ijms22136907Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico ApproachMaria L. Lozano0Cristina Segú-Vergés1Mireia Coma2María T. Álvarez-Roman3José R. González-Porras4Laura Gutiérrez5David Valcárcel6Nora Butta7Hospital General Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CB15/00055-CIBERER, 30007 Murcia, SpainAnaxomics Biotech S.L., Diputació 237, 1°, 1<sup>a</sup>, 08007 Barcelona, SpainAnaxomics Biotech S.L., Diputació 237, 1°, 1<sup>a</sup>, 08007 Barcelona, SpainUnidad de Trombosis y Hemostasia, Servicio de Hematología, Hospital Universitario La Paz, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, SpainUnidad de Hemostasia y Trombosis, Servicio de Hematología, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente, 58-182, 37007 Salamanca, SpainGrupo de Investigación en Plaquetas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Departamento de Medicina, Universidad de Oviedo, 33071 Oviedo, SpainServicio Hematología, Vall d´Hebron Insitute of Oncology (VHIO), Hospital Univesitario Vall d’Hebron, Universitat Autònoma de Barcelona, Centro Cellex, Natzaret, 115-117, 08035 Barcelona, SpainInstituto de Investigación HospitaUniversitario La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, SpainEltrombopag 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.https://www.mdpi.com/1422-0067/22/13/6907eltrombopagprimary immune thrombocytopeniaimmunomodulationin silicosystems biologymathematical modelling |
| spellingShingle | Maria L. Lozano Cristina Segú-Vergés Mireia Coma María T. Álvarez-Roman José R. González-Porras Laura Gutiérrez David Valcárcel Nora Butta Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach International Journal of Molecular Sciences eltrombopag primary immune thrombocytopenia immunomodulation in silico systems biology mathematical modelling |
| title | Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach |
| title_full | Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach |
| title_fullStr | Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach |
| title_full_unstemmed | Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach |
| title_short | Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach |
| title_sort | elucidating the mechanism of action of the attributed immunomodulatory role of eltrombopag in primary immune thrombocytopenia an in silico approach |
| topic | eltrombopag primary immune thrombocytopenia immunomodulation in silico systems biology mathematical modelling |
| url | https://www.mdpi.com/1422-0067/22/13/6907 |
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