Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms

Autor(es):Mostrar menos -

Machado-Neto, Joao Agostinho ^{[1, 2]} ; Fenerich, Bruna Alves ^[2] ; Scopim-Ribeiro, Renata ^[2] ; Eide, Christopher A. ^{[3, 4]} ; Coelho-Silva, Juan Luiz ^[2] ; Porto Dechandt, Carlos Roberto ^[5] ; Fernandes, Jaqueline Cristina ^[2] ; Nunes Rodrigues Alves, Ana Paula ^[2] ; Scheucher, Priscila Santos ^[2] ; Simoes, Belinda Pinto ^[2] ; Alberici, Luciane Carla ^[5] ; de Figueiredo Pontes, Lorena Lobo ^[2] ; Tognon, Cristina E. ^{[3, 4]} ; Druker, Brian J. ^{[3, 4]} ; Rego, Eduardo Magalhaes ^[2] ; Traina, Fabiola ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto, SP - Brazil

^[3] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 - USA

^[4] Howard Hughes Med Inst, Portland, OR - USA

^[5] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH & DISEASE; v. 9, FEB 22 2018.
• Citações Web of Science: 2

Resumo

The recurrent gain-of-function JAK2(V617F) mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2(V617F)-positive cells. In JAK2(V617F)-expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2(V617F) tumor burden and splenomegaly in Jak2(V617F) knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN. (AU)

• 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: 14/23092-0 - Investigação da função da proteína IRS2 em células hematopoéticas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado