Targeting GD2 ganglioside and aurora A kinase as a dual strategy leading to cell death in cultures of human neuroblastoma cells

Cancer Lett. 2013 Dec 1;341(2):248-64. doi: 10.1016/j.canlet.2013.08.018. Epub 2013 Aug 17.

Abstract

The mechanism of the inhibitory effect of anti-GD2 ganglioside (GD2) 14G2a mouse monoclonal antibody (mAb) on human neuroblastoma cells survival was studied in vitro. It was recently shown in IMR-32 cells that death induced by this antibody exhibited several characteristics typical of apoptosis. In this study we used cytotoxixity assays, qRT-PCR and immunoblotting to evaluate the response of several human neuroblastoma cell lines to the anti-GD2 14G2a mAb. We showed that the mAb decreases all three aurora kinases expression and phosphorylation in IMR-32 and LA-N-1 cells. Most importantly, we show, that MK-5108 specific aurora A kinase inhibitor decreases neuroblastoma cell survival, and when used in combination with the mAb, significantly potentiates cytotoxicity against IMR-32, CHP-134, and LA-N-5 neuroblastoma cells in vitro. It was shown that downregulation of aurora A kinase by the therapeutic antibody is associated with decreased levels of MYCN protein in cytoplasm, and induced expression of PHLDA1 and P53 proteins.

Keywords: Aurora kinases; GD2 ganglioside; Monoclonal antibody; Neuroblastoma; P53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / genetics
  • Aurora Kinase A / metabolism
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Flow Cytometry
  • Gangliosides / antagonists & inhibitors*
  • Gangliosides / immunology
  • Gangliosides / metabolism
  • Gene Expression / drug effects
  • Humans
  • Immunoblotting
  • Mice
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
  • Antibodies, Monoclonal
  • Cyclohexanecarboxylic Acids
  • Gangliosides
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • PHLDA1 protein, human
  • Protein Kinase Inhibitors
  • TP53 protein, human
  • Thiazoles
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • ganglioside, GD2
  • Aurora Kinase A
  • Caspase 3
  • Caspase 7