Formononetin acts synergistically with a JAK2 inhibitor to suppress growth in myeloproliferative neoplasm by inhibiting JAK/STAT3 signaling pathway

Abstract

Purpose: To determine the effect of formononetin (FMNT) in the proliferation, drug resistance, and DNA damage of myeloproliferative  neoplasm (MPN), and to evaluate the potential of FMNT as a therapeutic target. Methods: Cell viability curves and colony formation assays were used to characterize the proliferation of HEL or HEL/R cells. Flow  cytometry was conducted to assess the apoptosis of HEL or HEL/R cells, while western blotting was performed to evaluate the  expressions of DNA H2AX, DNA-PK, and Rad51, which are indicative of DNA damage, and the phosphorylation levels of JAK2 and STAT3  were determined. Results: Formononetin (FMNT) suppressed cell proliferation of HEL cells in a dose-dependent manner. It significantly reduced colony  formation and promoted apoptosis of HEL cells (p < 0.05). For HEL/R cells, FMNT treatment significantly reduced cell viability, and  resistance, and promoted apoptosis. Moreover, FMNT elevated H2AX levels and significantly reduced the expressions of DNA-PK and Rad51 in TG101209 (TG)-induced JAK-TKI-resistant cells (p < 0.05). Furthermore, FMNT decreased JAK2 and STAT3 phosphorylation in JAK- TKI-resistant cells. Conclusion: Treatment with FMNT represses proliferation, promotes apoptosis, weakens JAK-TKI resistance, and  strengthens DNA damage in MPN cells by suppressing JAK/STAT3 pathway. This suggests that FMNT is a potential therapeutic candidate  for the treatment of MPN.