ONTD induces growth arrest and apoptosis of human hepatoma Bel-7402 cells though a peroxisome proliferator-activated receptor γ-dependent pathway. (December 2017)

• Record Type: Journal Article
• Authors: Tan, Jiani; Shen, Weixing; Shi, Wenjing; Chen, Xi; Sun, Dongdong; Xu, Changliang; Yan, Qiuying; Cheng, Haibo; Lai, Yisheng; Ji, Hui
• Is Part Of: Toxicology in vitro. Volume 45:Part 1(2017)
• Page Start: 44
• Page End: 53
• Publication Date: 2017-12
• Subjects: ONTD 3-Oxo-29-noroleana-1, 9(11), 12-trien-2, 20-dicarbonitrile -- GA glycyrrhetinic acid -- PTEN phosphatase and tensin homologue deleted on chromosome ten -- HCC hepatocellular carcinoma -- PPAR-γ Peroxisome proliferator-activated receptor gamma -- DMEM Dulbecco's Modified Eagle's Medium -- DMSO dimethylsulfoxide -- FBS fetal bovine serum -- JC-1 5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolo-carbocyanine iodide -- PI propidium iodide -- AST aspartate aminotransferase -- ALT alanine aminotransferase -- ALP alkaline phosphatase -- BUN Blood urea nitrogen; Hepatocellular carcinoma -- Cell cycle -- PPAR-γ -- PTEN/Akt signaling pathway; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2017.08.012
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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. Highlights: ONTD inhibits the viability and the growth of human hepatoma cells. ONTD increased in ROS production and reduced mitochondrial membrane potential. ONTD induces G0/G1 cell cycle arrest in human hepatoma Bel-7402 cells. PTEN and PI3K/Akt pathways activation contributes to ONTD-induced cell cycle arrest. PPAR-γ-dependent pathway activation contributes to ONTD-induced cell cycle arrest.