Vitamin K3 derivative induces apoptotic cell death in neuroblastoma via downregulation of MYCN expression
Hiroyuki Yoda1, Toshimitsu Nakayama2, Motofumi Miura3
1Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
Abstract:
Neuroblastoma is a pediatric malignant tumor arising from the sympathetic nervous system. The patients with high-risk neuroblastomas frequently exhibit amplification and high expression of the MYCN gene, resulting in worse clinical outcomes. Vitamin K3 (VK3) is a synthetic VK-like compound that has been known to have antitumor activity against various types of cancers. In the present study, we have asked whether VK3 and its derivative, VK3-OH, could have the antitumor activity against neuroblastoma-derived cells. Based on our results, VK3-OH strongly inhibited cell proliferation and induced apoptotic cell death compared to VK3. Treatment of MYCN-driven neuroblastoma cells with VK3-OH potentiated tumor suppressor p53 accompanied by downregulation of anti-apoptotic Bcl-2 and Mcl-1. Interestingly, VK3-OH also suppressed the MYCN at mRNA and protein levels. Furthermore, we found downregulation of LIN28B following VK3-OH treatment in MYCN-amplified and overexpressed neuroblastoma cells. Collectively, our current findings strongly suggest that VK3-OH provides a potential therapeutic strategy for patients with MYCN-driven neuroblastomas.
Insights
Vitamin K3-OH effectively combats neuroblastoma by inhibiting cell growth and inducing apoptosis. This compound targets MYCN-driven tumors, offering a promising new therapeutic strategy for pediatric cancer.
Area of Science:
- Oncology
- Pediatric Malignancies
- Cancer Therapeutics
Background:
- Neuroblastoma, a pediatric cancer of the sympathetic nervous system, often presents with poor prognosis in high-risk cases.
- MYCN gene amplification and overexpression are key drivers of aggressive neuroblastoma and worse clinical outcomes.
- Vitamin K3 (VK3), a synthetic compound, exhibits known antitumor properties across various cancer types.
Purpose of the Study:
- To investigate the potential antitumor activity of Vitamin K3 (VK3) and its derivative, VK3-OH, against neuroblastoma cells.
- To evaluate the efficacy of VK3-OH in MYCN-driven neuroblastoma models.
Main Methods:
- Treatment of neuroblastoma-derived cells with VK3 and VK3-OH.
- Assessment of cell proliferation, apoptosis, and expression of key proteins (p53, Bcl-2, Mcl-1, MYCN, LIN28B).
- Analysis of MYCN gene and protein levels in MYCN-amplified neuroblastoma cells.
Main Results:
- VK3-OH demonstrated significantly stronger inhibition of cell proliferation and induction of apoptotic cell death compared to VK3.
- VK3-OH treatment upregulated tumor suppressor p53 and downregulated anti-apoptotic proteins Bcl-2 and Mcl-1 in MYCN-driven neuroblastoma cells.
- VK3-OH suppressed MYCN at both mRNA and protein levels and downregulated LIN28B in MYCN-amplified neuroblastoma cells.
Conclusions:
- VK3-OH exhibits potent antitumor activity against neuroblastoma cells, particularly those driven by MYCN.
- The compound's mechanisms involve inducing apoptosis, modulating key cancer-related proteins, and suppressing MYCN.
- VK3-OH represents a promising therapeutic candidate for treating MYCN-driven high-risk neuroblastomas.
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