Vitamin K3 derivative induces apoptotic cell death in neuroblastoma via downregulation of MYCN expression

Hiroyuki Yoda; Toshimitsu Nakayama; Motofumi Miura; Masaharu Toriyama; Shigeyasu Motohashi; Takashi Suzuki

doi:10.1016/j.bbrep.2019.100701

Vitamin K3 derivative induces apoptotic cell death in neuroblastoma via downregulation of MYCN expression

Biochem Biophys Rep. 2019 Oct 31:20:100701. doi: 10.1016/j.bbrep.2019.100701. eCollection 2019 Dec.

Authors

Hiroyuki Yoda¹, Toshimitsu Nakayama², Motofumi Miura³, Masaharu Toriyama³, Shigeyasu Motohashi³, Takashi Suzuki^{1

4}

Affiliations

¹ Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
² Center for Pharmacist Education, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
³ Laboratory of Molecular Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
⁴ Department of Pediatrics and Child Health, School of Medicine, Nihon University, 30-1 Oyaguchikami, Itabashi-ku, Tokyo, 173-0032, 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.

Keywords: Bcl-2; LIN28B; MYCN; Mcl-1; Neuroblastoma; Vitamin K3.