Department of Neurological Surgery, Clinical Science Center, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792-3232, USA.
Neurochem Res. 2012 Apr;37(4):671-9. doi: 10.1007/s11064-011-0659-z. Epub 2011 Nov 22.
Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine (PC)-specific phospholipase C (PC-PLC). D609 also inhibits sphingomyelin synthase (SMS). PC-PLC and/or SMS inhibition will affect lipid second messengers 1,2-diacylglycerol (DAG) and/or ceramide. Evidence indicates either PC-PLC and/or SMS inhibition affected the cell cycle and arrested proliferation, and stimulated differentiation in various in vitro and in vivo studies. Xanthogenate compounds are also potent antioxidants and D609 reduced Aß-induced toxicity, attributed to its antioxidant properties. Zn²⁺ is necessary for PC-PLC enzymatic activity; inhibition by D609 might be attributed to its Zn²⁺ chelation. D609 has also been proposed to inhibit acidic sphingomyelinase or down-regulate hypoxia inducible factor-1α; however these are down-stream events related to PC-PLC inhibition. Characterization of the mammalian PC-PLC is limited to inhibition of enzymatic activity (frequently measured using Amplex red assay with bacterial PC-PLC as a standard). The mammalian PC-PLC has not been cloned; sequenced and structural information is unavailable. D609 showed promise in cancer studies, reduced atherosclerotic plaques (inhibition of PC-PLC) and cerebral infarction after stroke (PC-PLC or SMS). D609 actions as an antagonist to pro-inflammatory cytokines have been attributed to PC-PLC. The purpose of this review is to comprehensively evaluate the literature and summarize the findings and relevance to cell cycle and CNS pathologies.
三环癸烷-9-基黄原酸酯（D609）具有抗病毒和抗肿瘤特性。D609 的作用广泛归因于抑制磷脂酰胆碱（PC）特异性磷脂酶 C（PC-PLC）。D609 还抑制鞘磷脂合酶（SMS）。PC-PLC 和/或 SMS 抑制将影响脂质第二信使 1,2-二酰基甘油（DAG）和/或神经酰胺。有证据表明，PC-PLC 和/或 SMS 抑制作用影响细胞周期并阻止增殖，并在各种体外和体内研究中刺激分化。黄原酸化合物也是有效的抗氧化剂，D609 减少 Aβ诱导的毒性，归因于其抗氧化特性。Zn²⁺是 PC-PLC 酶活性所必需的；D609 的抑制可能归因于其对 Zn²⁺的螯合作用。D609 还被提议抑制酸性鞘磷脂酶或下调缺氧诱导因子-1α；然而，这些是与 PC-PLC 抑制相关的下游事件。哺乳动物 PC-PLC 的特性仅限于酶活性的抑制（通常使用 Amplex red 测定法并用细菌 PC-PLC 作为标准进行测量）。哺乳动物 PC-PLC 尚未被克隆；测序和结构信息不可用。D609 在癌症研究中显示出希望，减少动脉粥样硬化斑块（PC-PLC 抑制）和中风后脑梗死（PC-PLC 或 SMS）。PC-PLC 拮抗促炎细胞因子的作用归因于 D609。本综述的目的是全面评估文献并总结发现及其与细胞周期和中枢神经系统病理学的相关性。
