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High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition

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Title: High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition
Authors: Laurel T. Bate-Eya, Ilona J.M. den Hartog, Ida van der Ploeg, Linda Schild, Jan Koster, Evan E. Santo, Ellen M. Westerhout, Rogier Versteeg, Huib N. Caron, Jan J. Molenaar, M. Emmy M. Dolman
Source: Oncotarget
Publisher Information: Impact Journals, LLC, 2016.
Publication Year: 2016
Subject Terms: Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors, 0301 basic medicine, Sulfonamides/pharmacology, Cell Survival, Heterocyclic/pharmacology, Drug Evaluation, Preclinical, Apoptosis, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Cell Line, Cytochromes c/metabolism, Bridged Bicyclo Compounds, Inhibitory Concentration 50, Mice, Neuroblastoma, 03 medical and health sciences, Cell Line, Tumor, Mitochondria/metabolism, Antineoplastic Combined Chemotherapy Protocols, Neuroblastoma/drug therapy, Animals, Humans, Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors, Sulfonamides, Tumor, Bcl-2-Like Protein 11, Apoptosis/drug effects, Cytochromes c, Bridged Bicyclo Compounds, Heterocyclic, Xenograft Model Antitumor Assays, Preclinical, Mitochondria, 3. Good health, Treatment Outcome, Proto-Oncogene Proteins c-bcl-2, Drug Evaluation, Myeloid Cell Leukemia Sequence 1 Protein, Female, Bcl-2-Like Protein 11/metabolism, Cell Survival/drug effects, Research Paper
Description: The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression.
Document Type: Article
Other literature type
Language: English
ISSN: 1949-2553
DOI: 10.18632/oncotarget.8547
Access URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=8547&path%5B%5D=25438
https://pubmed.ncbi.nlm.nih.gov/27056887
https://research-portal.uu.nl/en/publications/a6040dda-e642-4807-902f-066fa70f7d2a
https://doi.org/10.18632/oncotarget.8547
https://www.ncbi.nlm.nih.gov/pubmed/27056887
https://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=8547
https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=8547&path%5B%5D=25438
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=8547
https://researchinformation.amsterdamumc.org/en/publications/high-efficacy-of-the-bcl-2-inhibitor-abt199-venetoclax-in-bcl-2-h
https://europepmc.org/article/MED/27056887
Rights: CC BY
Accession Number: edsair.doi.dedup.....9574a9f53255b9988b87b6405d8d092f
Database: OpenAIRE
Description
Abstract:The anti-apoptotic protein B cell lymphoma/leukaemia 2 (BCL-2) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression.
ISSN:19492553
DOI:10.18632/oncotarget.8547