TY - JOUR
T1 - Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms
AU - MacHado-Neto, Joaõ Agostinho
AU - Fenerich, Bruna Alves
AU - Scopim-Ribeiro, Renata
AU - Eide, Christopher A.
AU - Coelho-Silva, Juan Luiz
AU - Dechandt, Carlos Roberto Porto
AU - Fernandes, Jaqueline Cristina
AU - Rodrigues Alves, Ana Paula Nunes
AU - Scheucher, Priscila Santos
AU - Simões, Belinda Pinto
AU - Alberici, Luciane Carla
AU - De Figueiredo Pontes, Lorena Lôbo
AU - Tognon, Cristina E.
AU - Druker, Brian J.
AU - Rego, Eduardo Magalhães
AU - Traina, Fabiola
N1 - Funding Information:
Funding for this work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 402587/2016-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2014/ 23092-0; 2015/02200-2). The authors would like to thank Cleide Lúcia Araújo Silva and Silvia Elena Sanchez Mendoza for their valuable technical assistance in animal experiments and Vani Maria Alves Correa for her valuable technical
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/1
Y1 - 2018/3/1
N2 - The recurrent gain-of-function JAK2V617F 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 JAK2V617F-positive cells. In JAK2V617F-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 JAK2V617F tumor burden and splenomegaly in Jak2V617F 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.
AB - The recurrent gain-of-function JAK2V617F 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 JAK2V617F-positive cells. In JAK2V617F-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 JAK2V617F tumor burden and splenomegaly in Jak2V617F 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.
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U2 - 10.1038/s41419-017-0256-4
DO - 10.1038/s41419-017-0256-4
M3 - Article
C2 - 29472557
AN - SCOPUS:85042537484
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - 311
ER -