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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 publication




Journal article



Publication Date





27946 - 27958


ABT199, BCL-2, MCL-1, neuroblastoma, resistance, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Bcl-2-Like Protein 11, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Cell Survival, Cytochromes c, Drug Evaluation, Preclinical, Female, Humans, Inhibitory Concentration 50, Mice, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neuroblastoma, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Treatment Outcome, Xenograft Model Antitumor Assays