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Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms.
Cell Death Dis 2018; 9(3):311CD

Abstract

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.

Authors+Show Affiliations

Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil. Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Howard Hughes Medical Institute, Portland, OR, USA.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Howard Hughes Medical Institute, Portland, OR, USA.Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Howard Hughes Medical Institute, Portland, OR, USA.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil. ftraina@fmrp.usp.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29472557

Citation

Machado-Neto, João Agostinho, et al. "Metformin Exerts Multitarget Antileukemia Activity in JAK2V617F-positive Myeloproliferative Neoplasms." Cell Death & Disease, vol. 9, no. 3, 2018, p. 311.
Machado-Neto JA, Fenerich BA, Scopim-Ribeiro R, et al. Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms. Cell Death Dis. 2018;9(3):311.
Machado-Neto, J. A., Fenerich, B. A., Scopim-Ribeiro, R., Eide, C. A., Coelho-Silva, J. L., Dechandt, C. R. P., ... Traina, F. (2018). Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms. Cell Death & Disease, 9(3), p. 311. doi:10.1038/s41419-017-0256-4.
Machado-Neto JA, et al. Metformin Exerts Multitarget Antileukemia Activity in JAK2V617F-positive Myeloproliferative Neoplasms. Cell Death Dis. 2018 02 22;9(3):311. PubMed PMID: 29472557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms. AU - Machado-Neto,João 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, Y1 - 2018/02/22/ PY - 2017/05/02/received PY - 2017/12/21/accepted PY - 2017/12/20/revised PY - 2018/2/24/entrez PY - 2018/2/24/pubmed PY - 2018/2/24/medline SP - 311 EP - 311 JF - Cell death & disease JO - Cell Death Dis VL - 9 IS - 3 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. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/29472557/Metformin_exerts_multitarget_antileukemia_activity_in_JAK2V617F_positive_myeloproliferative_neoplasms_ L2 - http://dx.doi.org/10.1038/s41419-017-0256-4 DB - PRIME DP - Unbound Medicine ER -