Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells

Int Immunopharmacol. 2008 Jul;8(7):974-81. doi: 10.1016/j.intimp.2008.02.013. Epub 2008 Mar 26.

Abstract

The objective of this study was to assess the effect of ursolic acid, a triterpene on inducing apoptosis in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentration of ursolic acid showed the presence of apoptotic bodies and induced DNA fragmentation in a dose depended manner. The apoptotic genes p53 and caspase-3 were found to be upregulated while the anti-apoptotic gene bcl-2 was down regulated in ursolic acid treated cells. The transcription factors NF-kappaBp65, NF-kappaBp50, NF-kappaBc-Rel, c-FOS, ATF-2 and CREB-1 were found to be inhibited significantly (p<0.001) in ursolic acid treated cells compared to untreated control. The pro-inflammatory cytokine production and gene expression of TNF-alpha, IL-1beta, IL-6 and GM-CSF were down regulated in ursolic acid treated cells compared to nontreated B16F-10 metastatic melanoma cells. All these results demonstrate that ursolic acid induce apoptosis via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways.

MeSH terms

  • Activating Transcription Factor 2 / antagonists & inhibitors
  • Animals
  • Apoptosis / drug effects*
  • Caspase 3 / genetics*
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, bcl-2*
  • Genes, p53*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • Triterpenes / pharmacology*
  • Ursolic Acid

Substances

  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • Cytokines
  • NF-kappa B
  • Triterpenes
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Caspase 3