Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms

Joaõ Agostinho MacHado-Neto, Bruna Alves Fenerich, Renata Scopim-Ribeiro, Christopher A. Eide, Juan Luiz Coelho-Silva, Carlos Roberto Porto Dechandt, Jaqueline Cristina Fernandes, Ana Paula Nunes Rodrigues Alves, Priscila Santos Scheucher, Belinda Pinto Simões, Luciane Carla Alberici, Lorena Lôbo De Figueiredo Pontes, Cristina E. Tognon, Brian J. Druker, Eduardo Magalhães Rego, Fabiola Traina

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article number311
JournalCell Death and Disease
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    MacHado-Neto, J. A., Fenerich, B. A., Scopim-Ribeiro, R., Eide, C. A., Coelho-Silva, J. L., Dechandt, C. R. P., Fernandes, J. C., Rodrigues Alves, A. P. N., Scheucher, P. S., Simões, B. P., Alberici, L. C., De Figueiredo Pontes, L. L., Tognon, C. E., Druker, B. J., Rego, E. M., & Traina, F. (2018). Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms. Cell Death and Disease, 9(3), [311]. https://doi.org/10.1038/s41419-017-0256-4