Lladó Victoria, López David J, Ibarguren Maitane, Alonso María, Soriano Joan B, Escribá Pablo V, Busquets Xavier
Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands-Lipopharma Therapeutics, S.L., Palma, Spain.
Epidemiology and Clinical Research, CIMERA, Mallorca, Spain.
Biochim Biophys Acta. 2014 Jun;1838(6):1619-27. doi: 10.1016/j.bbamem.2014.01.027. Epub 2014 Feb 10.
This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis. In addition in some cancer cells, the increases in SM are associated with Fas receptor (FasR) capping and ligand-free induction of apoptosis. In glioma cell lines, the increases in SM are associated with the inhibition of the Ras/MAPK and PI3K/Akt pathways, in association with p27Kip1 overexpression. Finally, an analysis of the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database for glioma patient survival shows that the weight of SM-related metabolism gene expression in glioma patients' survival is similar to glioma-related genes. Due to its low toxicity and anti-tumoral effect in cell and animal models its status as an orphan drug for glioma treatment by the European Medicines Agency (EMA) was recently acknowledged and a phase 1/2A open label, non-randomized study was started in patients with advanced solid tumors including malignant glioma. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
本综述总结了2-羟基油酸（NaCHOleate；2OHOA；Minerval）对神经胶质瘤和其他类型肿瘤作用的细胞基础。NaCHOleate可激活鞘磷脂合酶（SGMS），增加细胞膜鞘磷脂（SM）和二酰基甘油（DAG）的水平，同时降低磷脂酰乙醇胺（PE）和磷脂酰胆碱（PC）的水平。NaCHOleate自身以及DAG膜水平的增加会诱导蛋白激酶C（PKC）的易位和过表达，随后细胞周期蛋白D、细胞周期蛋白依赖性激酶4和6（CDK 4和6）减少，视网膜母细胞瘤蛋白发生低磷酸化，E2F1受到抑制，二氢叶酸还原酶（DHFR）被敲低，从而损害DNA合成。此外，在一些癌细胞中，SM的增加与Fas受体（FasR）聚集以及无配体诱导的细胞凋亡有关。在神经胶质瘤细胞系中，SM的增加与Ras/MAPK和PI3K/Akt信号通路的抑制有关，并伴有p27Kip1的过表达。最后，对神经胶质瘤患者生存的分子脑肿瘤数据储存库（REMBRANDT）数据库进行分析表明，神经胶质瘤患者生存中与SM相关的代谢基因表达权重与神经胶质瘤相关基因相似。由于其在细胞和动物模型中具有低毒性和抗肿瘤作用，欧洲药品管理局（EMA）最近认可其作为神经胶质瘤治疗孤儿药的地位，并启动了一项1/2A期开放标签、非随机研究，纳入包括恶性神经胶质瘤在内的晚期实体瘤患者。本文是名为：膜结构与功能：在细胞生理学、病理学和治疗中的相关性的特刊的一部分。
