Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3

Cancer Lett. 2009 Feb 8;274(1):132-42. doi: 10.1016/j.canlet.2008.09.013. Epub 2008 Oct 25.

Abstract

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-alpha (TNF-alpha), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-alpha-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-alpha-induced NF-kappaB activation through the inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-kappaB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-alpha-induced NF-kappaB activation through the suppression of IkappaBalpha degradation, leading to reduced expression of NF-kappaB-regulated gene products. Combined treatment with SFN and TNF-alpha was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-alpha-induced NF-kappaB activity and induces apoptosis through activation of ROS-dependent caspase-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3 / metabolism*
  • Cell Proliferation / drug effects
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation / drug effects*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • I-kappa B Proteins / metabolism
  • Isothiocyanates
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphorylation / drug effects
  • Reactive Oxygen Species / metabolism*
  • Thiocyanates / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Anticarcinogenic Agents
  • I-kappa B Proteins
  • Isothiocyanates
  • NF-kappa B
  • NFKBIA protein, human
  • Reactive Oxygen Species
  • Thiocyanates
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Caspase 3
  • sulforafan