Didymin: an orally active citrus flavonoid for targeting neuroblastoma
Sharad S Singhal1, Sulabh Singhal2, Preeti Singhal3
1Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, USA.
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.
Insights
Didymin, a natural compound, effectively targets and eliminates drug-resistant neuroblastoma cells, including those with p53 mutations. This compound shows promise as a safe, oral treatment for refractory neuroblastoma, potentially altering current therapeutic approaches.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Neuroblastoma is a common childhood cancer, with p53-mutant forms exhibiting high treatment resistance.
- MYCN amplification is frequent in neuroblastoma and its function is linked to p53.
- Drug-resistant neuroblastoma poses a significant clinical challenge.
Purpose of the Study:
- To investigate the efficacy of didymin, a citrus-derived compound, against neuroblastoma, particularly p53-mutant and drug-resistant forms.
- To elucidate the molecular mechanisms underlying didymin's anti-neuroblastoma activity.
- To assess the therapeutic potential and safety of didymin for refractory neuroblastoma.
Main Methods:
- In vitro studies using neuroblastoma cell lines (p53 wild-type and mutant).
- In vivo studies using neuroblastoma xenograft mouse models.
- Analysis of RKIP (Raf-inhibitory protein) regulation and its role in didymin's action.
- Investigation of didymin's effects on MYCN, GRK2, PKCs, Let-7 micro-RNA, and endocytosis pathways.
Main Results:
- Didymin demonstrated potent cytotoxicity against both p53 wild-type and p53-mutant neuroblastoma cells.
- Oral administration of didymin led to significant regression of neuroblastoma xenografts in mice.
- Didymin exhibited no toxicity to non-malignant cells, neural tissues, or neural stem cells.
- Didymin upregulates RKIP, which mediates inhibition of MYCN and other key signaling molecules.
Conclusions:
- Didymin effectively overcomes drug resistance in p53-mutant neuroblastoma via RKIP-mediated inhibition of MYCN.
- Didymin's multifaceted mechanism involves both Raf-dependent and -independent pathways.
- Didymin represents a promising, safe, and orally available agent for refractory neuroblastoma, with potential to change treatment paradigms.
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