Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3388330
- author
- 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.
- organization
- publishing date
- 2012
- 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
- Elsevier
- external identifiers
-
- wos:000310569100018
- scopus:84867575920
- pmid:22366560
- 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
- 2016-04-01 10:38:37
- date last changed
- 2022-01-26 01:07:45
@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}}, keywords = {{Neuroblastoma; BCL2; Apoptosis; Cancer; ABT263}}, language = {{eng}}, number = {{16}}, pages = {{3093--3103}}, publisher = {{Elsevier}}, 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}}, doi = {{10.1016/j.ejca.2012.01.037}}, volume = {{48}}, year = {{2012}}, }