ONTD induces growth arrest and apoptosis of human hepatoma Bel-7402 cells though a peroxisome proliferator-activated receptor γ-dependent pathway.

ONTD (3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has been reported to exhibit anti-inflammatory and anti-tumor activities through its mechanisms are not fully understood. Previously, we demonstrated that ONTD induces apoptosis of human hepatoma cells via a MAPK-dependent mitochondrial pathway. Recently, ONTD was found to increase sub-G1 accumulation and Annexin-V positive staining, indicating apoptotic induction effect. It was also be found that ONTD increase the PPAR-γ activity, reduce the phosphorylation of Akt and increase phosphatase and tensin homologue (PTEN) protein expression in hepatocellular carcinoma (HCC) Bel-7402 cells, and these were associated with the inhibition of cells proliferation. More importantly, these effects could be diminished by GW9662, a specific PPAR-γ antagonist, suggesting that ONTD can act as a ligand of PPAR-γ. Taken together, our novel observations suggested that ONTD may have potential implication in HCC prevention and treatment, and showed for the first time that the anti-tumor effect of ONTD may also be mediated through modulation of the PPAR-γ activation and mediated by the PTEN/Akt signaling pathway. The present study also supports ONTD as a potential drug candidate for chemoprevention or chemotherapy of HCC.