School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, Tianjin, 30072, China.
Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hawaii, 96720, USA.
Biochem Biophys Res Commun. 2019 Aug 27;516(3):733-738. doi: 10.1016/j.bbrc.2019.06.123. Epub 2019 Jun 26.
Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC against the NB cell lines. These results may lead to safer and more effective treatment options for NB patients especially for those with high-risk NB.
神经母细胞瘤（NB）是一种起源于神经嵴细胞的神经内分泌肿瘤。大约 90%的病例发生在 5 岁以下的儿童中。MYCN 的扩增与高危神经母细胞瘤相关，与没有 MYCN 扩增的患者相比，具有 MYCN 扩增的患者预后更差。在这项研究中，从圆柏中分离出的三种化合物对具有和没有四环素诱导的 MYCN 过表达的 NB 细胞系显示出抗增殖活性，它们被鉴定为（-）-脱氧鬼臼毒素（1）、（-）-马兜铃内脂（2）和（+）-异贝壳杉烯酸（3）。化合物 2 和 3 在 NB 细胞中的作用包括降低 NB 细胞活力和诱导细胞凋亡。化合物 1 在过表达 MycN 的 NB 细胞中更有效。化合物 1 还在 M2(+)细胞中几乎诱导了 2 倍的细胞内游离钙水平增加，这可能表明该化合物的作用机制不同。对人胚肾细胞（HEK-293）的细胞毒性研究表明，化合物 1、2 和 3 在接近其对 NB 细胞系的 IC 的浓度下对非癌细胞无效。这些结果可能为 NB 患者，特别是高危 NB 患者提供更安全、更有效的治疗选择。
