Fenretinide, which mediates apoptosis in neuroblastoma cells, is being considered as a novel therapeutic for neuroblastoma. The cytotoxic mechanisms of fenretinide, however, have not been fully elucidated. Sustained-activation of JNK and p38 MAPK signaling has been shown recently to have a pivotal role in stress-induced apoptosis. Whether fenretinide activates the signaling in neuroblastoma cells is not known. In the present study, fenretinide induced sustained-activation of both JNK and p38 MAPK in neuroblastoma cells. Pretreatment with the antioxidant L-ascorbic acid almost completely inhibited the accumulation of fenretinide-induced intracellular reactive oxygen species (ROS), activation of JNK and p38 MAPK and apoptosis. Intracellular ROS production and activation of stress signaling was not altered by fenretinide in resistant neuroblastoma cells. Our study demonstrates that in neuroblastoma cells, fenretinide induces sustained-activation of JNK and p38 MAPK in an ROS-dependent manner and indicates that JNK and p38 MAPK signaling might mediate fenretinide-induced apoptosis. Our results also indicate that suppression of the fenretinide-induced ROS productive system and the downstream JNK and p38 MAPK signaling pathways causes neuroblastoma cells to become resistant to fenretinide.
Copyright 2004 Wiley-Liss, Inc.