Inhibition of pyruvate dehydrogenase kinase‑1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming

Int J Oncol. 2020 Sep;57(3):733-742. doi: 10.3892/ijo.2020.5098. Epub 2020 Jul 10.


The Warburg effect is a unique metabolic feature of the majority of tumor cells and is closely related to chemotherapeutic resistance. Pyruvate dehydrogenase kinase 1 (PDK1) is considered a 'switch' that controls the fate of pyruvate in glucose metabolism. However, to date, to the best of our knowledge, there are only a few studies to available which had studied the reduction of chemotherapeutic resistance via the metabolic reprogramming of tumor cells with PDK1 as a target. In the present study, it was found dicoumarol (DIC) reduced the phosphorylation of pyruvate dehydrogenase (PDH) by inhibiting the activity of PDK1, which converted the metabolism of human hepatocellular carcinoma (HCC) cells to oxidative phosphorylation, leading to an increase in mitochondrial reactive oxygen species ROS (mtROS) and a decrease in mitochondrial membrane potential (MMP), thereby increasing the apoptosis induced by oxaliplatin (OXA). Furthermore, the present study elucidated that the targeting of PDK1 may be a potential strategy for targeting metabolism in the chemotherapy of HCC. In addition, DIC as an 'old drug' exhibits novel efficacy, bringing new hope for antitumor therapy.

Keywords: apoptosis; glucose metabolism; hepatocellular carcinoma; pyruvate dehydrogenase kinase 1; Warburg effect; chemotherapeutic resistance.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dicumarol / pharmacology*
  • Dicumarol / therapeutic use
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Oxaliplatin / pharmacology
  • Oxaliplatin / therapeutic use
  • Oxidative Phosphorylation / drug effects
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / antagonists & inhibitors*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
  • Reactive Oxygen Species / metabolism
  • Warburg Effect, Oncologic / drug effects
  • Xenograft Model Antitumor Assays


  • PDK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Reactive Oxygen Species
  • Oxaliplatin
  • Dicumarol