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Published on: October 10, 2025
Effect of bortezomib on human neuroblastoma: analysis of molecular mechanisms involved in cytotoxicity
Valérie Combaret1, Sandrine Boyault, Isabelle Iacono
1Laboratoire de Recherche Translationnelle, Centre Léon Bérard, Lyon, France. combaret@lyon.fnclcc.fr
Background:
Bortezomib, a specific and selective inhibitor of the 26S proteasome with antitumor activity against a wide range of malignancies, has been approved for the treatment of relapsed or refractory multiple myeloma and other cancers. Recently, bortezomib has been identified as an effective inhibitor of neuroblastoma cell growth and angiogenesis.
Results:
In the present study, we demonstrate that some neuroblastoma cell lines are actually resistant to bortezomib. We have sought to characterize the main pathway by which proteasome inhibition leads to apoptosis, and to define the mechanism responsible for resistance to bortezomib in neuroblastoma cells. Our results show that SB202190, an inhibitor of mitogen-activated protein kinase (MAPK) p38, enhances the ability of bortezomib to induce apoptosis by preventing the phosphorylation of the heat shock protein (HSP) 27.
Conclusion:
This study opens the way to further clinical investigations and suggests a potential benefit of using a combination of bortezomib with an inhibitor of p38 MAPK for the treatment of neuroblastoma relapse.
Insights
Neuroblastoma cells can resist bortezomib treatment. Combining bortezomib with a p38 MAPK inhibitor enhances apoptosis, offering a new strategy for neuroblastoma relapse treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Bortezomib, a proteasome inhibitor, shows antitumor activity and inhibits neuroblastoma growth.
- Neuroblastoma cell lines exhibit varying sensitivity to bortezomib.
- Understanding resistance mechanisms is crucial for effective neuroblastoma treatment.
Purpose of the Study:
- To characterize the apoptosis pathway induced by proteasome inhibition in neuroblastoma.
- To identify mechanisms of bortezomib resistance in neuroblastoma cells.
- To evaluate combination therapy for overcoming resistance.
Main Methods:
- Investigated proteasome inhibition-induced apoptosis.
- Utilized SB202190, a p38 MAPK inhibitor.
- Assessed heat shock protein (HSP) 27 phosphorylation.
Main Results:
- Some neuroblastoma cell lines are resistant to bortezomib.
- SB202190 enhances bortezomib-induced apoptosis.
- Inhibition of p38 MAPK prevents HSP 27 phosphorylation, sensitizing cells to bortezomib.
Conclusions:
- Bortezomib resistance in neuroblastoma involves complex pathways.
- Combination therapy with p38 MAPK inhibitors may overcome bortezomib resistance.
- This approach warrants further clinical investigation for neuroblastoma relapse.
