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.
Original language | English |
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Pages (from-to) | 27946-58 |
Number of pages | 13 |
Journal | Oncotarget |
Volume | 7 |
Issue number | 19 |
DOIs | |
Publication status | Published - 10 May 2016 |
Keywords
- Animals
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Apoptosis/drug effects
- Bcl-2-Like Protein 11/metabolism
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- Cytochromes c/metabolism
- Drug Evaluation, Preclinical
- Female
- Humans
- Inhibitory Concentration 50
- Mice
- Mitochondria/metabolism
- Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
- Neuroblastoma/drug therapy
- Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
- Sulfonamides/pharmacology
- Treatment Outcome
- Xenograft Model Antitumor Assays