Effect of bortezomib on human neuroblastoma: analysis of molecular mechanisms involved in cytotoxicity

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.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.Neuroblastoma (NB) accounts for 8% to 10% of childhood cancers [1]. The two main prognostic factors are age and stage [2,3]. Localized NB and those arising in infants have a 90% survival rate, except in cases of MYCN amplification where survival is below 30% [3-5]. Approximately 50% of all NB occurring in children older than 1 year are metastatic at diagnosis. NB is considered chemosensitive. Chemotherapy is indicated in localized NB for patients with large primary tumors in whom tumor chemoreduction allows safer surgical excision [6,7], as well as in metastatic NB to achieve complete remission of metastases. The most effective drugs are alkylating agents, platinum compounds, anthracyclines and epipodophyllotoxins [8]. High-dose chemotherapy followed by hematopoietic stem cell transplantation and maintenance therapy with retinoic acid improve survival by 35% in children with metastatic NB [9,10], but the 5-year event-free survival rate remains below 50%. Therefore, novel therapeutic approaches are needed.The multicatalytic ubiquitin-proteasome pathway is responsible for the degradation of eukaryotic cellular proteins [11-14]. This adenosine 5'-triphosphate-dependent process is vital for normal cell cycling, function and survival, making proteasome inhibition