| Texto completo | |
| Autor(es): |
Fernandes, Jaqueline Cristina
;
Fenerich, Bruna Alves
;
Alves-Silva, Antonio Bruno
;
Fonseca, Natasha Peixoto
;
Coelho-Silva, Juan Luiz
;
Scheucher, Priscila Santos
;
Rego, Eduardo Magalhaes
;
Figueiredo-Pontes, Lorena Lobo
;
Machado-Neto, Joao Agostinho
;
Traina, Fabiola
Número total de Autores: 10
|
| Tipo de documento: | Artigo Científico |
| Fonte: | TOXICOLOGY IN VITRO; v. 83, p. 7-pg., 2022-05-26. |
| Resumo | |
Myeloproliferative neoplasms (MPN) belong to a group of clonal diseases of hematopoietic stem cells characterized by aberrant proliferation of mature myeloid lineages. The constitutive activation of the JAK2/STAT signaling pathway is now well established to play a central role in MPN pathogenesis; however, accumulating evidence now indicates that the IGF1R-mediated signaling pathway contributes to the maintenance of the malignant phenotype. Studies using inhibitors of IGF1-mediated signaling have reported cytotoxic effects in cellular and murine models of MPN, but no consensus has been reached regarding the potency and efficacy of inhibitors of the IGF1R-related pathway in this context. In the present study, we compared the potency and efficacy of three inhibitors of IGF1R-related pathways in a JAK2(V617F)-driven cellular model. These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2(V617F) cells, with NT157 showing the greatest potency. Both the induction of apoptosis and reduction in cell proliferation were associated with the observed reduction in cell viability. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN. (AU) | |
| Processo FAPESP: | 13/08135-2 - CTC - Centro de Terapia Celular |
| Beneficiário: | Dimas Tadeu Covas |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |
| Processo FAPESP: | 17/19864-6 - Investigação da participação das proteínas IRS1 e IRS2 na hematopoese normal e síndrome mielodisplásica utilizando modelos murinos e células-tronco hematopoéticas humanas |
| Beneficiário: | Fabíola Traina |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 15/02200-2 - Investigação funcional da participação de IRS2 em neoplasias mieloproliferativas crônicas BCR-ABL1 negativas |
| Beneficiário: | Fabíola Traina |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 16/14049-0 - Investigação de mutações na via IGF1R/IRS em Neoplasia Mieloproliferativa e o efeito de inibidores farmacológicos desta via de sinalização em modelo murino knockin para a mutação JAK2V617F |
| Beneficiário: | Jaqueline Cristina Fernandes |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas |
| Beneficiário: | João Agostinho Machado Neto |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |