Abstract
Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases. Didymin is a citrus-derived natural compound that kills p53 wild-type as well as drug-resistant p53-mutant neuroblastoma cells in culture. In addition, orally administered didymin causes regression of neuroblastoma xenografts in mouse models, without toxicity to non-malignant cells, neural tissues, or neural stem cells. RKIP is a Raf-inhibitory protein that regulates MYCN activation, is transcriptionally upregulated by didymin, and appears to play a key role in the anti-neuroblastoma actions of didymin. In this review, we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2, PKCs, Let-7 micro-RNA, and clathrin-dependent endocytosis by Raf-dependent and -independent mechanisms. In addition, we will discuss studies supporting potential clinical impact and translation of didymin as a low cost, safe, and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma.
Highlights
Among childhood malignancies, neuroblastomas (NB) constitute the most common solid tumors in infants and the third most common class of pediatric malignancies [1,2,3,4]
We found that Raf-kinase inhibitory protein (RKIP), which regulates MYCN activation, is transcriptionally upregulated by didymin and appears to play a key role in the anti-NB actions of didymin [15]
Our algorithms are based on the theory that cell cycle and receptor-ligand signaling are linked by the mercapturic acid pathway (MAP), because the rate of endocytosis-dependent internalization of receptor-ligand pairs is directly proportional to the rate of flux of metabolites in the MAP [24]
Summary
Neuroblastomas (NB) constitute the most common solid tumors in infants and the third most common class of pediatric malignancies [1,2,3,4]. Lin et al showed that didymin significantly ameliorated chronic liver injury and collagen deposition and attenuated the mitochondrial membrane potential accompanied by release of cytochrome C These actions were mediated by inhibition of the ERK/MAPK and PI3K/Akt pathways by regulation of RKIP expression. It is likely that didymin www.impactjournals.com/oncotarget contributes to a basal protective effect against oncogenic transformation in normal tissue That didymin had these effects on N-Myc and RKIP expression in normal mice brain without affecting the mature neuronal and neural stem cell population, together with the ability of didymin to exert similar effects in NB xenografts [15], strongly indicate the mechanistic relevance of didymin for both primary and tertiary management of NB. They sought to use a three-dimensional homology model of N-Myc and didymin, generated using the Schrodinger software suite, to validate the active ligand binding mode, based on mutation analysis, in order to better understand the mechanism of action of didymin and to spur rational design for lead optimization (Figure 4)
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