A direct comparison of selective BH3-mimetics reveals BCL-XL, BCL-2 and MCL-1 as promising therapeutic targets in neuroblastoma.

Abstract

BACKGROUND:

Despite advances in the treatment of neuroblastoma, patients with high-risk disease still have dismal survival prognosis. Neuroblastoma cells display elevated expression of the antiapoptotic BCL-2 proteins, suggesting that BH3-mimetics may be a promising treatment option. Here, we investigated the role of BCL-2, BCL-XL and MCL-1 in neuroblastoma.

METHODS:

A panel of neuroblastoma cell lines and primary patient-derived cells were exposed to BH3-mimetics targeting BCL-2 (ABT-199), BCL-XL (A1331852) or MCL-1 (S63845). In addition, protein expression and interaction patterns were analysed using Western blotting and immunoprecipitation.

RESULTS:

All tested BH3-mimetics were able to induce apoptosis in neuroblastoma cell lines, indicating that not only BCL-2 but also BCL-XL and MCL-1 may be promising therapeutic targets. Primary patient-derived cells displayed highest sensitivity to A1331852, highlighting the important role of BCL-XL in neuroblastoma. Further analysis into the molecular mechanisms of apoptosis revealed that A1331852 and S63845 displaced proapoptotic proteins like BIM and BAK from their antiapoptotic targets, subsequently leading to the activation of BAX and BAK and caspase-dependent apoptosis.

CONCLUSIONS:

By using selective BH3-mimetics, this study demonstrates that BCL-2, BCL-XL, and MCL-1 are all relevant therapeutic targets in neuroblastoma. A1331852 and S63845 induce rapid apoptosis that is initiated following a displacement of BAK from BCL-XL or MCL-1, respectively.

• Authors: Annika Bierbrauer, Maureen Jacob, Meike Vogler, Simone Fulda
• Journal: British journal of cancer (Br J Cancer) Vol. 122 Issue 10 Pg. 1544-1551 (05 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 32203216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAK1 protein, human
• BCL2 protein, human
• Bax protein (53-86)
• Bcl-2-Like Protein 11
• Bridged Bicyclo Compounds, Heterocyclic
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• S63845
• Sulfonamides
• Thiophenes
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-X Protein
• venetoclax

Topics

• Apoptosis (drug effects)
• Bcl-2-Like Protein 11 (genetics)
• Biomimetics
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics)
• Neuroblastoma (drug therapy, genetics, pathology)
• Peptide Fragments (pharmacology)
• Proto-Oncogene Proteins (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics)
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Thiophenes (pharmacology)
• bcl-2 Homologous Antagonist-Killer Protein (genetics)
• bcl-X Protein (genetics)