Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-κB in colon cancer cells

Mol Carcinog. 2012 Jun;51(6):475-90. doi: 10.1002/mc.20812. Epub 2011 Jun 15.

Abstract

Nimbolide, a plant-derived limonoid has been shown to exert its antiproliferative effects in various cell lines. We demonstrate that nimbolide effectively inhibited proliferation of WiDr colon cancer cells through inhibition of cyclin A leading to S phase arrest. It also caused activation of caspase-mediated apoptosis through the inhibition of ERK1/2 and activation of p38 and JNK1/2. Further nimbolide effectively retarded tumor cell migration and invasion through inhibition of metalloproteinase-2/9 (MMP-2/9) expression, both at the mRNA and protein level. It was also a strong inhibitor of VEGF expression, promoter activity, and in vitro angiogenesis. Finally, nimbolide suppressed the nuclear translocation of p65/p50 and DNA binding of NF-κB, which is an important transcription factor for controlling MMP-2/9 and VEGF gene expression.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Caspases / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Cyclin A / antagonists & inhibitors
  • Cyclin D1 / antagonists & inhibitors
  • Down-Regulation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Limonins / chemistry
  • Limonins / pharmacology*
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Cyclin A
  • Limonins
  • NF-kappa B
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Cyclin D1
  • nimbolide
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9