Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1-RAGE and AKT pathways

Biochem Biophys Res Commun. 2014 Jan 24;443(4):1162-8. doi: 10.1016/j.bbrc.2013.12.064. Epub 2013 Dec 19.

Abstract

Ethyl pyruvate (EP) was recently identified as a stable lipophilic derivative of pyruvic acid with significant antineoplastic activities. The high mobility group box-B1 (HMGB1)-receptor for advanced glycation end-products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. We tried to observe the effects of ethyl pyruvate on liver cancer growth and explored its effects in hepatocellular carcinoma model. In this study, three hepatocellular carcinoma cell lines were treated with ethyl pyruvate. An MTT colorimetric assay was used to assess the effects of EP on cell proliferation. Flow cytometry and TUNEL assays were used to analyze apoptosis. Real-time PCR, Western blotting and immunofluorescence demonstrated ethyl pyruvate reduced the HMGB1-RAGE and AKT pathways. The results of hepatoma orthotopic tumor model verified the antitumor effects of ethyl pyruvate in vivo. EP could induce apoptosis and slow the growth of liver cancer. Moreover, EP decreased the expression of HMGB1, RAGE, p-AKT and matrix metallopeptidase-9 (MMP9) and increased the Bax/Bcl-2 ratio. In conclusion, this study demonstrates that ethyl pyruvate induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells, plays a critical role in the treatment of cancer.

Keywords: Apoptosis; Ethyl pyruvate; Hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Glycation End Products, Advanced / metabolism*
  • HMGB1 Protein / metabolism*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Nude
  • Oncogene Protein v-akt / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyruvates / pharmacology*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • BAX protein, human
  • Glycation End Products, Advanced
  • HMGB1 Protein
  • HMGB1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Pyruvates
  • bcl-2-Associated X Protein
  • ethyl pyruvate
  • Oncogene Protein v-akt
  • MMP9 protein, human
  • Matrix Metalloproteinase 9