Fig. 8

Overview of the potential mechanisms involved in the DpC-mediated effects on neuroblastoma. DpC increases TNFα expression in neuroblastoma cells, which may (1) activate cytotoxic T cells to destroy tumor cells and/or (2) acts on the TNFα receptor (TNFR) to activate down-stream signaling pathways. These include the MAPK/p38/JNK and NF-ĸB signaling cascades, which lead to nuclear transcription of numerous genes, including those that induce apoptosis, as well as cytokines such as TNFα. Activation of TNFR also promotes cleavage of caspase 8, leading to caspase 3 cleavage and subsequent apoptosis. Moreover, DpC is also highly redox active, resulting in the production of reactive oxygen species (ROS) [13]. The generation of ROS triggers the release of cytochrome c from mitochondria [8], leading to cleavage of caspase 9, which then also cleaves caspase 3, leading to apoptosis. Further, the increased ROS also leads to upregulation of neuroglobin (Ngb) and cytoglobin (Cygb) expression as both of these proteins respond to oxidative stress. Together, these molecular effects, which promote apoptosis, could contribute to the anti-cancer activity of DpC in neuroblastoma