Tricyclodecan-9-yl-xanthogenate (D609) mechanism of actions: a mini-review of literature

Abstract

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.

Figure 1

D609 chemical structure

Figure 2

PC hydrolysis by PC-PLC and PLD. D609 inhibits PC-PLC, attenuating DAG release and subsequent PA formation [17]. PA can be directly formed via PC hydrolysis by PLD. Modified from ref [34].

Figure 3

PC-PLC hydrolyzes PC to form DAG and phosphocholine. DAG stimulates ASMase and release of ceramide from SM. SM synthase transfers the phosphocholine head group from PC to ceramide to form SM and DAG. D609 inhibits PC-PLC [3] and/or SMS [31]. Modified from ref [25].

Figure 4

Multiple pathways may be affected by D609 through targeting SMS/PC-PLC [3, 31]. Modified from ref [34]. D609 may increase de novo ceramide synthesis by stimulating SPT [33]. D609 antioxidant properties are based on Aβ induced oxidative stress [48], effects on cystine/glutamate antiporter are based on glutamate toxicity in immature hippocampal neurons [22], increase in metabolic activity in 264.7 macrophages is based on MTT assay. D609 could decrease formation of ROS and oxidized PC (OxPC) by inhibiting proliferation of microglia/macrophages. Alternatively, D609 could attenuate ROS/OxPC generation through its antioxidant/glutathione mimetic properties. D609 inhibited PC synthesis and may directly affect membrane translocation of CCT, the rate-limiting enzyme in PC synthesis [51]. Studies indicated that inhibition of PC-PLC by D609 enhanced PLD activity [23]. Bacterial PC-PLC is a monomeric enzyme which accommodates three Zn²⁺ ions in the active site likely to be involved in the binding to the substrate and essential for the enzymatic activity [27]. Does D609 inhibition of PC-PLC activity by Zn²⁺ chelation need to be addressed?