Metformin demonstrates antileukemic activity and may have clinical implications for the treatment of myeloproliferative neoplasms (MPN) in combination with ruxolitinib, according to a study published in Cell Death & Disease.

The JAK1/2 inhibitor ruxolitinib demonstrates clinical activity among patients with MPN (eg, essential thrombocythemia, primary myelofibrosis, polycythemia vera), but rarely produces a complete response. Data from previous studies have shown that metformin may selectively inhibit hematologic malignant cells.

For this study, researchers assessed the activity of metformin and ruxolitinib alone or in combination in various human lines, including the JAK2V617F-positive cell lines HEL and SET2.

Assay results showed that metformin alone reduced cell viability in a dose- and time-dependent manner, and further analysis of metformin and ruxolitinib alone confirmed significantly reduced cell viability.

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In combination, ruxolitinib and metformin demonstrated a synergistic effect and significantly reduced cell viability compared to monotherapy. Additional investigations revealed metformin plus ruxolitinib increased apoptotic activity, reduced cell proliferation, clonogenicity, cellular oxygen, suspended the cell cycle, and completely inhibited colony formation.

Metformin therapy also reduced tumor burden in Ba/F3 JAK2V617F, splenomegaly in Jak2V617F knock-in-induced MPN mice, and inhibited spontaneous erythroid colony formation in primary cells from patients with polycythemia vera.

The authors concluded that this “exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN.”                                                   

Reference

Machado-Neto JA, Fenerich BA, Scopim-Ribeiro, et al. Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms [published online February 22, 2018]. Cell Death Dis. doi: 10.1038/s41419-017-0256