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Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms
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 ruxolitin...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833553/ https://www.ncbi.nlm.nih.gov/pubmed/29472557 http://dx.doi.org/10.1038/s41419-017-0256-4 |
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author | Machado-Neto, João Agostinho Fenerich, Bruna Alves Scopim-Ribeiro, Renata Eide, Christopher A. Coelho-Silva, Juan Luiz Dechandt, Carlos Roberto Porto Fernandes, Jaqueline Cristina Rodrigues Alves, Ana Paula Nunes Scheucher, Priscila Santos Simões, Belinda Pinto Alberici, Luciane Carla de Figueiredo Pontes, Lorena Lôbo Tognon, Cristina E. Druker, Brian J. Rego, Eduardo Magalhães Traina, Fabiola |
author_facet | Machado-Neto, João Agostinho Fenerich, Bruna Alves Scopim-Ribeiro, Renata Eide, Christopher A. Coelho-Silva, Juan Luiz Dechandt, Carlos Roberto Porto Fernandes, Jaqueline Cristina Rodrigues Alves, Ana Paula Nunes Scheucher, Priscila Santos Simões, Belinda Pinto Alberici, Luciane Carla de Figueiredo Pontes, Lorena Lôbo Tognon, Cristina E. Druker, Brian J. Rego, Eduardo Magalhães Traina, Fabiola |
author_sort | Machado-Neto, João Agostinho |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5833553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58335532018-03-06 Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms Machado-Neto, João Agostinho Fenerich, Bruna Alves Scopim-Ribeiro, Renata Eide, Christopher A. Coelho-Silva, Juan Luiz Dechandt, Carlos Roberto Porto Fernandes, Jaqueline Cristina Rodrigues Alves, Ana Paula Nunes Scheucher, Priscila Santos Simões, Belinda Pinto Alberici, Luciane Carla de Figueiredo Pontes, Lorena Lôbo Tognon, Cristina E. Druker, Brian J. Rego, Eduardo Magalhães Traina, Fabiola Cell Death Dis Article 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. Nature Publishing Group UK 2018-02-22 /pmc/articles/PMC5833553/ /pubmed/29472557 http://dx.doi.org/10.1038/s41419-017-0256-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Machado-Neto, João Agostinho Fenerich, Bruna Alves Scopim-Ribeiro, Renata Eide, Christopher A. Coelho-Silva, Juan Luiz Dechandt, Carlos Roberto Porto Fernandes, Jaqueline Cristina Rodrigues Alves, Ana Paula Nunes Scheucher, Priscila Santos Simões, Belinda Pinto Alberici, Luciane Carla de Figueiredo Pontes, Lorena Lôbo Tognon, Cristina E. Druker, Brian J. Rego, Eduardo Magalhães Traina, Fabiola Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title | Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title_full | Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title_fullStr | Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title_full_unstemmed | Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title_short | Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |
title_sort | metformin exerts multitarget antileukemia activity in jak2(v617f)-positive myeloproliferative neoplasms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833553/ https://www.ncbi.nlm.nih.gov/pubmed/29472557 http://dx.doi.org/10.1038/s41419-017-0256-4 |
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