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.