Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells

Oncogene. 2001 Mar 22;20(12):1476-85. doi: 10.1038/sj.onc.1204225.


The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Carcinoma / drug therapy*
  • Caspases / metabolism
  • Cell Survival
  • Colorectal Neoplasms / drug therapy*
  • Cytochrome c Group / metabolism
  • Drug Synergism
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / pharmacology*
  • Mitochondria / metabolism*
  • Models, Biological
  • Nitric Oxide / metabolism
  • Nitroprusside / pharmacology*
  • Oxidative Stress
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Apoptosis Regulatory Proteins
  • Cytochrome c Group
  • Membrane Glycoproteins
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Nitroprusside
  • Nitric Oxide
  • Caspases