ABSTRACT
PURPOSE: Neuroblastoma is the most common extracranial solid tumor of childhood. The retinoic acid analogue, fenretinide (4-hydroxyphenyl retinamide; 4-HPR), induces apoptosis in neuroblastoma cells in vitro and is currently in clinical trials for children with refractory neuroblastoma. We have previously shown that expression of the p75 neurotrophin receptor (p75NTR) enhances apoptosis induction and mitochondrial accumulation of reactive oxygen species by 4-HPR in neuroblastoma cells. We now examine the signaling events that underlie this effect. METHODS: Systematic examination of pro- and anti-apoptotic signaling effectors was performed by Western blot. Specific inhibitors of JNK phosphorylation and scavengers of mitochondrial reactive oxygen species were used to demonstrate the roles of these phenomena in the enhancement of fenretinide efficacy. RESULTS: The present studies demonstrate that enhancement of 4-HPR-induced apoptosis by p75NTR is dependent upon p38MAPK phosphorylation, JNK phosphorylation, caspase 3 activation, Akt cleavage, and decreased Akt phosphorylation. In addition, treatment with 4-HPR results in upregulation of MKK4 and MEKK1, and phosphorylation of MKK3/6. Efforts to enhance the efficacy of 4-HPR and to identify those tumors most likely to respond to it might exploit these effectors of 4-HPR-induced apoptosis. CONCLUSIONS: Pharmacological agents that enhance MKK4 or MEKK1 expression or JNK expression or phosphorylation may enhance efficacy of 4-HPR in neuroblastomas that do not express high levels of p75NTR.
Subject(s)
Antineoplastic Agents/pharmacology , Fenretinide/pharmacology , Nerve Tissue Proteins/metabolism , Neuroblastoma/drug therapy , Receptors, Nerve Growth Factor/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Down-Regulation/drug effects , Gene Knockdown Techniques , Humans , MAP Kinase Kinase 4/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neuroblastoma/metabolism , Neuroblastoma/pathology , Oncogene Protein v-akt/metabolism , Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Receptors, Nerve Growth Factor/deficiency , Receptors, Nerve Growth Factor/genetics , Signal Transduction/drug effects , Transfection , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Children with high-risk disease have a 3-year event-free survival rate of only 20%. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma. The aim of this article was to review and critically evaluate the pharmacotherapy of neuroblastoma, using peer reviewed and review literature from 2000-11. All peer reviewed, published human subject studies of therapy for neuroblastoma in children were included. Animal model and in vitro studies were included only if they added to the understanding of the mechanism of a proposed or existing human neuroblastoma therapy. Current therapeutic options for neuroblastoma involve insufficient differentiation of normal from neoplastic tissue. Critically needed new approaches will increasingly exploit targeting of therapy for unique characteristics of the neuroblastoma cell. Pharmacotherapy for neuroblastoma still suffers from an inadequate therapeutic window. Enhancement of toxicity for tumor and safety for normal tissues will entail innovation in targeting neuroblastoma cells and rescuing or protecting normal tissue elements.
