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


CONCLUSIONS
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.
Combaret
Valérie
V
Laboratoire de Recherche Translationnelle, Centre Léon Bérard, Lyon, France. combaret@lyon.fnclcc.fr
Boyault
Sandrine
S
Iacono
Isabelle
I
Brejon
Stéphanie
S
Rousseau
Raphaël
R
Puisieux
Alain
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018832:Molecular Chaperones; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007093:Imidazoles; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole