Yoda Hiroyuki, Nakayama Toshimitsu, Miura Motofumi, Toriyama Masaharu, Motohashi Shigeyasu, Suzuki Takashi
Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
Center for Pharmacist Education, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
Biochem Biophys Rep. 2019 Oct 31;20:100701. doi: 10.1016/j.bbrep.2019.100701. eCollection 2019 Dec.
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 -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.
神经母细胞瘤是一种起源于交感神经系统的儿科恶性肿瘤。高危神经母细胞瘤患者经常表现出MYCN基因的扩增和高表达，导致临床预后较差。维生素K3（VK3）是一种合成的类维生素K化合物，已知对多种类型的癌症具有抗肿瘤活性。在本研究中，我们探讨了VK3及其衍生物VK3-OH是否对神经母细胞瘤衍生细胞具有抗肿瘤活性。根据我们的结果，与VK3相比，VK3-OH强烈抑制细胞增殖并诱导凋亡性细胞死亡。用VK3-OH处理MYCN驱动的神经母细胞瘤细胞可增强肿瘤抑制因子p53，同时下调抗凋亡蛋白Bcl-2和Mcl-1。有趣的是，VK3-OH还在mRNA和蛋白质水平上抑制MYCN。此外，我们发现在扩增和过表达的神经母细胞瘤细胞中，VK3-OH处理后LIN28B表达下调。总的来说，我们目前的研究结果强烈表明，VK3-OH为MYCN驱动的神经母细胞瘤患者提供了一种潜在的治疗策略。
