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

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.

• Authors: Irena Horwacik, Małgorzata Durbas, Elżbieta Boratyn, Paulina Węgrzyn, Hanna Rokita
• Journal: Cancer letters (Cancer Lett) Vol. 341 Issue 2 Pg. 248-64 (Dec 01 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23962557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 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

Topics

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