The O-methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

J Cell Biochem. 2018 Sep;119(9):7377-7387. doi: 10.1002/jcb.27041. Epub 2018 May 15.


Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti-oxidant, anti-proliferative, and anti-tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case-control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti-cancer mechanism of formononetin in ovarian cancer are unknown. We investigated the toxicological mechanism of formononetin in ES2 and OV90 ovarian cancer cells. Formononetin suppressed cell proliferation through sub G0/G1 phase arrest and increased apoptosis in both cell lines. Furthermore, it induced loss of mitochondrial membrane potential and generation of reactive oxygen species in ES2 and OV90 cells. The formononetin-mediated regulation of cell proliferation and apoptosis involved decreased phosphorylation of ERK1/2, P90RSK, AKT, P70S6K, and S6 proteins, and increased phosphorylation of P38 protein in ES2 and OV90 cells. Co-treatment of formononetin with pharmacological inhibitors (LY294002 or U0126) revealed additional anti-proliferative effects on the two human ovarian cancer cell types. Conclusively, the results indicate the potential value of formononetin as an anti-cancer agent in human ovarian cancer.

Keywords: cell death mechanism; formononetin; ovarian cancer; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chromones / pharmacology
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Female
  • G1 Phase / drug effects*
  • Humans
  • Imidazoles / pharmacology
  • Isoflavones / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Matrix Metalloproteinases / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Resting Phase, Cell Cycle / drug effects*
  • Signal Transduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antineoplastic Agents
  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Imidazoles
  • Isoflavones
  • Morpholines
  • Nitriles
  • Pyridines
  • Reactive Oxygen Species
  • U 0126
  • formononetin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinases
  • SB 203580