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

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

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)27946-58
Number of pages13
JournalOncotarget
Volume7
Issue number19
DOIs
Publication statusPublished - 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

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