Role of reactive oxygen species-mediated mitochondrial dysregulation in 3-bromopyruvate induced cell death in hepatoma cells : ROS-mediated cell death by 3-BrPA

J Bioenerg Biomembr. 2008 Dec;40(6):607-18. doi: 10.1007/s10863-008-9188-0. Epub 2008 Dec 6.

Abstract

Hexokinase type II (HK II) is the key enzyme for maintaining increased glycolysis in cancer cells where it is overexpressed. 3-bromopyruvate (3-BrPA), an inhibitor of HK II, induces cell death in cancer cells. To elucidate the molecular mechanism of 3-BrPA-induced cell death, we used the hepatoma cell lines SNU449 (low expression of HKII) and Hep3B (high expression of HKII). 3-BrPA induced ATP depletion-dependent necrosis and apoptosis in both cell lines. 3-BrPA increased intracellular reactive oxygen species (ROS) leading to mitochondrial dysregulation. NAC (N-acetyl-L: -cysteine), an antioxidant, blocked 3-BrPA-induced ROS production, loss of mitochondrial membrane potential and cell death. 3-BrPA-mediated oxidative stress not only activated poly-ADP-ribose (PAR) but also translocated AIF from the mitochondria to the nucleus. Taken together, 3-BrPA induced ATP depletion-dependent necrosis and apoptosis and mitochondrial dysregulation due to ROS production are involved in 3-BrPA-induced cell death in hepatoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Hexokinase / antagonists & inhibitors*
  • Humans
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • Pyruvates / pharmacology
  • Reactive Oxygen Species / metabolism*

Substances

  • Pyruvates
  • Reactive Oxygen Species
  • bromopyruvate
  • Hexokinase