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Review
. 2017 Apr 25;8(17):29428-29441.
doi: 10.18632/onco_target.15204.

Didymin: an orally active citrus flavonoid for _targeting neuroblastoma

Sharad S Singhal  1 , Sulabh Singhal  2 , Preeti Singhal  3 , Jyotsana Singhal  1 , David Horne  1 , Sanjay Awasthi  4
Affiliations
Review

Didymin: an orally active citrus flavonoid for _targeting neuroblastoma

Sharad S Singhal et al. Onco_target. .

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.

Keywords: N-Myc, RKIP; didymin; neuroblastoma; p53.

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Conflict of interest statement

CONFLICTS OF INTEREST

No conflict of interest exists for any of the authors.

Figures

Figure 1
Figure 1. Chemical structure of didymin
Figure 2
Figure 2. Molecular pathways affected by didymin
Schematic showing MYCN down-regulation by didymin and based on network analyses of our proteomic studies that focused on cancer-related pathways active in NB cells. The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathways) is a cell-signaling pathway that plays a vital role in normal cell division and growth. Mutations that result in constitutive activation of the MAPK/ERK pathway have been implicated in a broad range of solid tumors and are associated with tumor resistance to standard cancer therapies. Inhibition of MEK, which is pivotal protein kinase in the MAPK/ERK pathway, may block growth of solid tumors and interfere with development of resistance. Didymin inhibits MYCN through Raf-dependent and -independent mechanisms by inhibiting CDE through RKIP, GRK, PKC, and the Let-7 micro-RNA.
Figure 3
Figure 3. Effect of didymin on neuroblastoma signaling pathways
Didymin inhibits N-Myc transcription, down-regulates PI3K, Akt, vimentin, and up-regulates RKIP. Didymin also down-regulates cyclin D1, CDK4 and cyclin B1, which is a down-stream effector of p53 mediated cell-cycle regulation. Didymin decreases expression of the angiogenic marker CD31, proliferation marker Ki67, and N-Myc in vivo as revealed by histopathological examination of resected tumors. Blue -Normal signal transduction, Green-Up regulation of signaling protein, Red-Inhibitory effect of didymin.
Figure 4
Figure 4. Didymin-NMyc three dimensional ternary homology model
Homology structure model of N-Myc derived from protein PDB database using 1NKP, with DNA labeled in grey, N-Myc aa382-464 residues labeled in blue, didymin labeled in magenta for carbon, red for oxygen, and white for hydrogen, and the ligand binding surface of N-Myc labeled in green. The model was constructed using Schrödinger Glide docking software and was energy minimized for exploring protein ligand binding mode and mutagenesis validations.
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