Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2(V617F) driven cells

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art_FERNANDES_Differential_cytotoxic_activity_of_pharmacological_inhibitors_of_IGF1Rrelated_2022.PDF (5.31 MB)
Citações na Scopus
0
Tipo de produção
article
Data de publicação
2022
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
PERGAMON-ELSEVIER SCIENCE LTD
Autores
FERNANDES, Jaqueline Cristina
FENERICH, Bruna Alves
ALVES-SILVA, Antonio Bruno
FONSECA, Natasha Peixoto
COELHO-SILVA, Juan Luiz
SCHEUCHER, Priscila Santos
FIGUEIREDO-PONTES, Lorena Lobo
MACHADO-NETO, Joao Agostinho
TRAINA, Fabiola
Citação
TOXICOLOGY IN VITRO, v.83, article ID 105384, 7p, 2022
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
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.
Palavras-chave
Myeloproliferative neoplasms, Insulin-like growth factor 1 receptor, JAK2V617F, Pharmacological inhibitors, Antineoplastic activity
URI
https://observatorio.fm.usp.br/handle/OPI/50423
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - LIM/31
Artigos e Materiais de Revistas Científicas - ODS/03