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Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth

Lamers, Fieke; Schild, Linda; den Hartog, Ilona J. M.; Ebus, Marli E.; Westerhout, Ellen M.; Øra, Ingrid LU ; Koster, Jan; Versteeg, Rogier; Caron, Huib N. and Molenaar, Jan J. (2012) In European Journal of Cancer 48(16). p.3093-3103
Abstract
Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is strongly elevated compared to normal tissues and other malignancies. Most neuroblastoma cell lines lack this high BCL2 expression. Only two neuroblastoma cell lines (KCNR and SJNB12) show BCL2 expression levels representative for neuroblastoma tumours. To validate BCL2 as a therapeutic target in neuroblastoma we employed lentivirally mediated shRNA. Silencing of BCL2 in KCNR and SJNB12 resulted in massive apoptosis, while cell lines with low BCL2... (More)
Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is strongly elevated compared to normal tissues and other malignancies. Most neuroblastoma cell lines lack this high BCL2 expression. Only two neuroblastoma cell lines (KCNR and SJNB12) show BCL2 expression levels representative for neuroblastoma tumours. To validate BCL2 as a therapeutic target in neuroblastoma we employed lentivirally mediated shRNA. Silencing of BCL2 in KCNR and SJNB12 resulted in massive apoptosis, while cell lines with low BCL2 expression were insensitive. Identical results were obtained by treatment of the neuroblastoma cell lines with the small molecule BCL2 inhibitor ABT263, which is currently being clinically evaluated. Combination assays of ABT263 with most classical cytostatics showed strong synergistic responses. Subcutaneous xenografts of a neuroblastoma cell line with high BCL2 expression in NMRI nu/nu mice showed a strong response to ABT263. These findings establish BCL2 as a promising drug target in neuroblastoma and warrant further evaluation of ABT263 and other BCL2 inhibiting drugs. (C) 2012 Elsevier Ltd. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Neuroblastoma, BCL2, Apoptosis, Cancer, ABT263
in
European Journal of Cancer
volume
48
issue
16
pages
3093 - 3103
publisher
IFAC & Elsevier Ltd.
external identifiers
  • wos:000310569100018
  • scopus:84867575920
ISSN
1879-0852
DOI
10.1016/j.ejca.2012.01.037
language
English
LU publication?
yes
id
0fc95c13-8341-4c30-b046-1db88c078f9d (old id 3388330)
date added to LUP
2013-02-01 07:03:33
date last changed
2017-09-24 03:16:16
@article{0fc95c13-8341-4c30-b046-1db88c078f9d,
  abstract     = {Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is strongly elevated compared to normal tissues and other malignancies. Most neuroblastoma cell lines lack this high BCL2 expression. Only two neuroblastoma cell lines (KCNR and SJNB12) show BCL2 expression levels representative for neuroblastoma tumours. To validate BCL2 as a therapeutic target in neuroblastoma we employed lentivirally mediated shRNA. Silencing of BCL2 in KCNR and SJNB12 resulted in massive apoptosis, while cell lines with low BCL2 expression were insensitive. Identical results were obtained by treatment of the neuroblastoma cell lines with the small molecule BCL2 inhibitor ABT263, which is currently being clinically evaluated. Combination assays of ABT263 with most classical cytostatics showed strong synergistic responses. Subcutaneous xenografts of a neuroblastoma cell line with high BCL2 expression in NMRI nu/nu mice showed a strong response to ABT263. These findings establish BCL2 as a promising drug target in neuroblastoma and warrant further evaluation of ABT263 and other BCL2 inhibiting drugs. (C) 2012 Elsevier Ltd. All rights reserved.},
  author       = {Lamers, Fieke and Schild, Linda and den Hartog, Ilona J. M. and Ebus, Marli E. and Westerhout, Ellen M. and Øra, Ingrid and Koster, Jan and Versteeg, Rogier and Caron, Huib N. and Molenaar, Jan J.},
  issn         = {1879-0852},
  keyword      = {Neuroblastoma,BCL2,Apoptosis,Cancer,ABT263},
  language     = {eng},
  number       = {16},
  pages        = {3093--3103},
  publisher    = {IFAC & Elsevier Ltd.},
  series       = {European Journal of Cancer},
  title        = {Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth},
  url          = {http://dx.doi.org/10.1016/j.ejca.2012.01.037},
  volume       = {48},
  year         = {2012},
}