Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

J Nutr Biochem. 2012 Dec;23(12):1583-91. doi: 10.1016/j.jnutbio.2011.10.012. Epub 2012 Mar 23.


α-Tocopheryl succinate (α-TOS) inhibits oxidative phosphorylation at the level of mitochondrial complex I and II, thus promoting cancer cell death through mitochondrial reactive oxygen species (ROS) generation. Redox imbalance activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor involved in cell protection and detoxification responses. Here we examined the involvement of heme oxygenase-1 (HO-1) in the regulation of nuclear factor κB (NF-κB) signaling by short exposure to α-TOS in prostate cancer cells. A short-term (4 h) exposure to α-TOS causes a significant reduction in cell viability (76%±9%) and a moderate rise in ROS production (113%±8%). α-TOS alters glutathione (GSH) homeostasis by inducing a biphasic effect, i.e., an early (1 h) decrease in intracellular GSH content (56%±20%) followed by a threefold rise at 4 h. α-TOS increases nuclear translocation and electrophile-responsive/antioxidant-responsive elements binding activity of Nrf2, resulting in up-regulation of downstream genes cystine-glutamic acid exchange transporter and HO-1, while decreasing NF-κB nuclear translocation. This effect is suppressed by the pharmacological inhibition of HO-1 and mimicked by the end-products of HO activity, i.e., bilirubin and carbon monoxide. Results suggest a little understood mechanism for α-TOS-induced inhibition of NF-κB nuclear translocation due to HO-1 up-regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Antioxidants / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Glutathione / metabolism
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Transport / drug effects
  • Reactive Oxygen Species / metabolism
  • alpha-Tocopherol / pharmacology*
  • alpha-Tocopherol / toxicity


  • Antineoplastic Agents
  • Antioxidants
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Glutathione
  • alpha-Tocopherol