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Tricyclodecan-9-yl-Xanthogenate (D609) Mechanism of Actions: A Mini-Review of Literature

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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.

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Abbreviations

ASMase:

Acidic sphingomyelinase

BDNF:

Brain derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

CCT:

Cytidine triphosphate (CTP):phosphocholine cytidylyltransferase

Cdk:

Cyclin dependent kinase

D609:

Tricyclodecan-9-yl-xanthogenate

DAG:

1,2-diacylglycerol

HER2:

Human epidermal growth factor receptor 2

IGF-1:

Insulin-like growth factor

LPS:

Lipopolysaccharide

OxPC:

Oxidized phosphatidylcholine

PA:

Phosphatidic acid

PC:

Phosphatidylcholine

PC-PLC:

PC-phospholipase C

PLC:

Phospholipase C

PLD:

Phospholipase D

ROS:

Reactive oxygen species

SM:

Sphingomyelin

SMS:

Sphingomyelin synthase

SPT:

Serine palmitoyl transferase

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

References

  1. Sauer G, Amtmann E, Melber K et al (1984) DNA and RNA virus species are inhibited by xanthates, a class of antiviral compounds with unique properties. Proc Natl Acad Sci 81:3263–3267

    Article  PubMed  CAS  Google Scholar 

  2. Muller-Decker K (1989) Interruption of TPA-induced signals by an antiviral and antitumoral xanthate compound: inhibition of a phospholipase C-type reaction. Biochem Biophys Res Commun 162:198–205

    Article  PubMed  CAS  Google Scholar 

  3. Amtmann E (1996) The antiviral, antitumoural xanthate D609 is a competitive inhibitor of phosphatidylcholine-specific phospholipase C. Drugs Exp Clin Res 22:287–294

    PubMed  CAS  Google Scholar 

  4. Amtmann E, Mayer FK, Pink H, et al (2010) LMV-601: effect on HPV-16 and HPV-18 infected human cervical carcinoma cells. 50th interscience conference on antimicrobial agents and chemotherapy (ICAAC 2010), Boston

  5. Clark MA, Shorr RG, Bomalaski JS (1986) Antibodies prepared to Bacillus cereus phospholipase C crossreact with a phosphatidylcholine preferring phospholipase C in mammalian cells. Biochem Biophys Res Commun 140:114–119

    Article  PubMed  CAS  Google Scholar 

  6. Wang N, Du CQ, Wang SS et al (2004) D609 induces vascular endothelial cells and marrow stromal cells differentiation into neuron-like cells. Acta Pharmacol Sin 25:442–446

    PubMed  CAS  Google Scholar 

  7. Wang N, Lv X, Su L et al (2006) D609 blocks cell survival and induces apoptosis in neural stem cells. Bioorg Med Chem Lett 16:4780–4783

    Article  PubMed  CAS  Google Scholar 

  8. Wang N, Xie K, Huo S et al (2007) Suppressing phosphatidylcholine-specific phospholipase C and elevating ROS level, NADPH oxidase activity and Rb level induced neuronal differentiation in mesenchymal stem cells. J Cell Biochem 100:1548–1557

    Article  PubMed  CAS  Google Scholar 

  9. Wang N, Sun C, Huo S et al (2008) Cooperation of phosphatidylcholine-specific phospholipase C and basic fibroblast growth factor in the neural differentiation of mesenchymal stem cells in vitro. Int J Biochem Cell Biol 40:294–306

    Article  PubMed  CAS  Google Scholar 

  10. Cheng Y, Zhao Q, Liu X et al (2006) Phosphatidylcholine-specific phospholipase C, p53 and ROS in the association of apoptosis and senescence in vascular endothelial cells. FEBS Lett 580:4911–4915

    Article  PubMed  CAS  Google Scholar 

  11. Liu X, Yin D, Zhang Y et al (2007) Vascular endothelial cell senescence mediated by integrin β4 in vitro. FEBS Lett 581:5337–5342

    PubMed  CAS  Google Scholar 

  12. Zhao J, Miao J, Zhao B et al (2005) Upregulating of Fas, integrin β4 and P53 and depressing of PC-PLC activity and ROS level in VEC apoptosis by safrole oxide. FEBS Lett 579:5809–5813

    PubMed  CAS  Google Scholar 

  13. Fu D, Ma Y, Wu W et al (2009) Cell-cycle-dependent PC-PLC regulation by APC/CCdc20-mediated ubiquitin-proteasome pathway. J Cell Biochem 107:686–696

    Article  PubMed  CAS  Google Scholar 

  14. Paris L, Cecchetti S, Spadaro F et al (2010) Inhibition of phosphatidylcholine-specific phospholipase C downregulates HER2 overexpression on plasma membrane of breast cancer cells. Breast Cancer Res 12:R27

    Article  PubMed  Google Scholar 

  15. Iorio E, Ricci A, Bagnoli M et al (2010) Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells. Cancer Res 70:2126–2135

    Article  PubMed  CAS  Google Scholar 

  16. Cecchetti S, Spadaro F, Lugini L et al (2007) Functional role of phosphatidylcholine-specific phospholipase C in regulating CD16 membrane expression in natural killer cells. Eur J Immunol 37:2912–2922

    Article  PubMed  CAS  Google Scholar 

  17. Chen C, Hu Q, Yan J et al (2007) Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1α and apoptotic genes in a middle cerebral artery occlusion induced focal ischemia rat model. J Neurochem 102:1831–1841

    Article  PubMed  CAS  Google Scholar 

  18. Monick MM, Carter AB, Gudmundsson G et al (1999) A phosphatidylcholine-specific phospholipase C regulates activation of p42/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages. J Immunol 162:3005–3012

    PubMed  CAS  Google Scholar 

  19. Monick MM, Mallampalli RK, Carter AB et al (2001) Ceramide regulates lipopolysaccharide-induced phosphatidylinositol 3-kinase and Akt activity in human alveolar macrophages. J Immunol 167:5977–5985

    PubMed  CAS  Google Scholar 

  20. Zhang F, Zhao G, Dong Z (2001) Phosphatidylcholine-specific phospholipase C and D in stimulation of RAW264.7 mouse macrophage-like cells by lipopolysaccharide. Intl Immunopharmacol 1:1375–1384

    Article  CAS  Google Scholar 

  21. Machleidt T, Kramer B, Adam D et al (1996) Function of the p55 TNF receptor “death domain” mediated by phosphatidylcholine-specific PLC. J Exp Med 184:725–733

    Article  PubMed  CAS  Google Scholar 

  22. Li YH, Maher P, Schubert D (1998) Phosphatidylcholine-specific phospholipase C regulates glutamate-induced nerve cell death. Proc Natl Acad Sci 95:7748–7753

    Article  PubMed  CAS  Google Scholar 

  23. Singh ATK, Radeff JM, Kunnel JG et al (2000) Phosphatidylcholine-specific phospholipase C inhibitor, tricyclodecan-9-yl xanthogenate (D609), increases phospholipase D-mediated phosphatidylcholine hydrolysis in UMR-106 osteoblastic osteosarcoma cells. Biochim Biophys Acta 1487:201–208

    PubMed  CAS  Google Scholar 

  24. Zhang L, Zhao J, Su L et al (2010) D609 inhibits progression of preexisting atheroma and promotes lesion stability in apolipoprotein E-/- mice. A role of phosphatidylcholine-specific phospholipase in atherosclerosis. Arterioscler Thromb Vasc Biol 30:411–418

    Article  PubMed  CAS  Google Scholar 

  25. Larsen EC, Hatcher JF, Adibhatla RM (2007) Effect of tricyclodecan-9-yl potassium xanthate (D609) on phospholipid metabolism and cell death during oxygen-glucose deprivation in PC12 cells. Neuroscience 146:946–961

    Article  PubMed  CAS  Google Scholar 

  26. Yu ZF, Nikolova-Karakashian M, Zhou DH et al (2000) Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J Mol Neurosci 15:85–97

    Article  PubMed  CAS  Google Scholar 

  27. Gonzalez-Bulnes P, Gonzalez-Roura A, Canals D et al (2010) 2-aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLC Bc . Bioorg Med Chem 18:8549–8555

    Article  PubMed  CAS  Google Scholar 

  28. Gonzalez-Roura A, Casas J, Llebaria A (2002) Synthesis and phospholipase C inhibitory activity of D609 diastereomers. Lipids 37:401–406

    Article  PubMed  CAS  Google Scholar 

  29. Tafesse FG, Ternes P, Holthuis JCM (2006) The multigenic sphingomyelin synthase family. J Biol Chem 281:29421–29425

    Article  PubMed  CAS  Google Scholar 

  30. Huitema K, van den Dikkenberg J, Brouwers JFHM et al (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23:33–44

    Article  PubMed  CAS  Google Scholar 

  31. Luberto C, Hannun YA (1998) SM synthase, a potential regulator of intracellular levels of ceramide and diacylglycerol during SV40 transformation. Does SM synthase account for the putative PC-specific PLC? J Biol Chem 273:14550–14559

    Article  PubMed  CAS  Google Scholar 

  32. Luberto C, Yoo DS, Suidan HS et al (2000) Differential effects of sphingomyelin hydrolysis and resynthesis on the activation of NF-kappa B in normal and SV40-transformed human fibroblasts. J Biol Chem 275:14760–14766

    Article  PubMed  CAS  Google Scholar 

  33. Perry RJ, Ridgway ND (2004) The role of de novo ceramide synthesis in the mechanism of action of the tricyclic xanthate D609. J Lipid Res 45:164–173

    Article  PubMed  CAS  Google Scholar 

  34. Adibhatla RM, Hatcher JF (2010) Protection by D609 through cell-cycle regulation after stroke. Mol Neurobiol 41:206–217

    Article  PubMed  CAS  Google Scholar 

  35. Dirkx E, Schwenk RW, Glatz JF et al (2011) High fat diet induced diabetic cardiomyopathy. Prostaglandins Leukot Essent Fatty Acids 85:219–225

    Article  PubMed  CAS  Google Scholar 

  36. Irie F, Hirabayashi Y (1998) Application of exogenous ceramide to cultured rat spinal motoneurons promotes survival or death by regulation of apoptosis depending on its concentrations. J Neurosci Res 54:475–485

    Article  PubMed  CAS  Google Scholar 

  37. Luberto C, Kraveka JM, Hannun YA (2002) Ceramide regulation of apoptosis versus differentiation: a walk on a fine line. Lessons from neurobiology. Neurochem Res 27:609–617

    Article  PubMed  CAS  Google Scholar 

  38. Riboni L, Viani P, Bassi R et al (2001) Basic fibroblast growth factor-induced proliferation of primary astrocytes. Evidence for the involvement of sphingomyelin biosynthesis. J Biol Chem 276:12797–12804

    Article  PubMed  CAS  Google Scholar 

  39. Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616

    Article  PubMed  CAS  Google Scholar 

  40. Claassen GF, Hann SR (2000) A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest. Proc Natl Acad Sci 97:9498–9503

    Article  PubMed  CAS  Google Scholar 

  41. Obaya AJ, Kotenko I, Cole MD et al (2002) The proto-oncogene c-myc acts through the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 to facilitate the activation of Cdk4/6 and early G1 phase progression. J Biol Chem 277:31263–31269

    Article  PubMed  CAS  Google Scholar 

  42. Lee JY, Bielawska AE, Obeid LM (2000) Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp Cell Res 261:303–311

    Article  PubMed  CAS  Google Scholar 

  43. Arnold HK, Sears RC (2006) Protein phosphatase 2A regulatory subunit B56α associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 26:2832–2844

    Article  PubMed  CAS  Google Scholar 

  44. Mufson RA, Gubina E, Rinaudo M et al (1998) A phosphatidylcholine phospholipase C inhibitor, D609, blocks interleukin-3 (IL-3)-induced bcl-2 expression but not c-myc expression in human IL-3-dependent cells. Exp Cell Res 240:228–235

    Article  PubMed  CAS  Google Scholar 

  45. Sultana R, Newman S, Mohmmad-Abdul H et al (2004) Protective effect of the xanthate, D609, on Alzheimer’s amyloid beta-peptide (1–42)-induced oxidative stress in primary neuronal cells. Free Radic Res 38:449–458

    Article  PubMed  CAS  Google Scholar 

  46. Sultana R, Newman SF, Abdul HM et al (2006) Protective effect of D609 against amyloid-β 1–42 induced oxidative modification of neuronal proteins: redox proteomics study. J Neurosci Res 84:409–417

    Article  PubMed  CAS  Google Scholar 

  47. Zhou DH, Lauderback CM, Yu T et al (2001) D609 inhibits ionizing radiation-induced oxidative damage by acting as a potent antioxidant. J Pharmacol Exp Ther 298:103–109

    PubMed  CAS  Google Scholar 

  48. Perluigi M, Joshi G, Sultana R et al (2006) In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid β-peptide (1–42)-induced oxidative stress. Neuroscience 138:1161–1170

    Article  PubMed  CAS  Google Scholar 

  49. Bai A, Meier GP, Wang Y et al (2004) Prodrug modification increases potassium tricyclo[5.2.1.0(2,6)]-decan-8-yl dithiocarbonate (D609) chemical stability and cytotoxicity against U937 leukemia cells. J Pharmacol Exp Ther 309:1051–1059

    Article  PubMed  CAS  Google Scholar 

  50. Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12:125–169

    Article  PubMed  CAS  Google Scholar 

  51. Ng MNP, Kitos TE, Cornell RB (2004) Contribution of lipid second messengers to the regulation of phosphatidylcholine synthesis during cell cycle re-entry. Biochim Biophys Acta 1686:85–99

    PubMed  CAS  Google Scholar 

  52. Antony P, Farooqui AA, Horrocks LA et al (2001) Effect of D609 on phosphatidylcholine metabolism in the nuclei of LA-N-1 neuroblastoma cells: a key role for diacylglycerol. FEBS Lett 509:115–118

    Article  PubMed  CAS  Google Scholar 

  53. Kang MS, Jung SY, Jung KM et al (2008) D609, an inhibitor of phosphatidylcholine-specific PLC, inhibits group IV cytosolic PLA2. Mol Cells 26:481–485

    PubMed  CAS  Google Scholar 

  54. Wiegmann K, Schutze S, Machleidt T et al (1994) Functional dichotomy of neutral and acidic sphingomyelinases in TNF-α signaling. Cell 78:1005–1015

    Article  PubMed  CAS  Google Scholar 

  55. Adibhatla RM, Hatcher JF (2008) Integration of cytokine biology and lipid metabolism in stroke. Front Biosci 13:1250–1270

    Article  PubMed  CAS  Google Scholar 

  56. Kalluri HSG, Dempsey RJ (2010) D609 inhibits the proliferation of neural progenitor cells. Neuroreport 21:700–703

    PubMed  CAS  Google Scholar 

  57. Lambertsen KL, Meldgaard M, Ladeby R et al (2005) A quantitative study of microglial-macrophage synthesis of tumor necrosis factor during acute and late focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25:119–135

    Article  PubMed  CAS  Google Scholar 

  58. Herrup K, Neve R, Ackerman SL et al (2004) Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 24:9232–9239

    Article  PubMed  CAS  Google Scholar 

  59. Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378

    Article  PubMed  CAS  Google Scholar 

  60. Katchanov J, Harms C, Gertz K et al (2001) Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J Neurosci 21:5045–5053

    PubMed  CAS  Google Scholar 

  61. Osuga H, Osuga S, Wang F et al (2000) Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci 97:10254–10259

    Article  PubMed  CAS  Google Scholar 

  62. Rashidian J, Iyirhiaro GO, Park DS (2007) Cell cycle machinery and stroke. Biochim Biophys Acta 1772:484–493

    PubMed  CAS  Google Scholar 

  63. Wang W, Bu B, Xie M et al (2009) Neural cell cycle dysregulation and central nervous system diseases. Prog Neurobiol 89:1–17

    Article  PubMed  CAS  Google Scholar 

  64. Yang Y, Herrup K (2007) Cell division in the CNS: protective response or lethal event in post-mitotic neurons? Biochim Biophys Acta 1772:457–466

    PubMed  CAS  Google Scholar 

  65. Khandelwal PJ, Herman AM, Moussa CE (2011) Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol 238:1–11

    Article  PubMed  CAS  Google Scholar 

  66. Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS inflammation. FEBS Lett (in press)

  67. Lalancette-Hebert M, Gowing G, Simard A et al (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605

    Article  PubMed  CAS  Google Scholar 

  68. Madinier A, Bertrand N, Mossiat C et al (2009) Microglial involvement in neuroplastic changes following focal brain ischemia in rats. PLoS ONE 4:e8101

    Article  PubMed  Google Scholar 

  69. Monk PN, Shaw PJ (2006) ALS: life and death in a bad neighborhood. Nat Med 12:885–887

    Article  PubMed  CAS  Google Scholar 

  70. Ekdahl CT, Kokaia Z, Lindvall O (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158:1021–1029

    Article  PubMed  CAS  Google Scholar 

  71. Schutze S, Potthoff K, Machleidt T et al (1992) TNF activates NF-κB by phosphatidylcholine-specific phospholipase C-induced ‘acidic’ sphingomyelin breakdown. Cell 71:765–776

    Article  PubMed  CAS  Google Scholar 

  72. Lv X, Su L, Yin D et al (2008) Knockdown of integrin [beta]4 in primary cultured mouse neurons blocks survival and induces apoptosis by elevating NADPH oxidase activity and reactive oxygen species level. Int J Biochem Cell Biol 40:689–699

    Article  PubMed  CAS  Google Scholar 

  73. Lv X, Wang N, Su L et al (2006) Inhibition of PC-PLC blocked the survival of mouse neural cells by up-regulating the expression of integrin beta4 and Rb. Dev Neurosci 28:499–504

    Article  PubMed  CAS  Google Scholar 

  74. Zhao J, Zhao B, Wang W et al (2007) Phosphatidylcholine-specific phospholipase C and ROS were involved in chicken blastodisc differentiation to vascular endothelial cells. J Cell Biochem 102:421–428

    Article  PubMed  CAS  Google Scholar 

  75. Zhang L, Li H, Li H et al (2011) Lipopolysaccharide activated phosphatidylcholine-specific phospholipase C and induced IL-8 and MCP-1 production in vascular endothelial cells. J Cell Physiol 226:1694–1701

    Article  PubMed  CAS  Google Scholar 

  76. Fantuzzi L, Spadaro F, Purificato C et al (2008) Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB-driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages. Blood 111:3355–3363

    Article  PubMed  CAS  Google Scholar 

  77. Ramoni C, Spadaro F, Menegon M et al (2001) Cellular localization and functional role of phosphatidylcholine-specific phospholipase C in NK cells. J Immunol 167:2642–2650

    PubMed  CAS  Google Scholar 

  78. Ramoni C, Spadaro F, Barletta B et al (2004) Phosphatidylcholine-specific phospholipase C in mitogen-stimulated fibroblasts. Exp Cell Res 299:370–382

    Article  PubMed  CAS  Google Scholar 

  79. Spadaro F, Ramoni C, Mezzanzanica D et al (2008) Phosphatidylcholine-specific phospholipase C activation in epithelial ovarian cancer cells. Cancer Res 68:6541–6549

    Article  PubMed  CAS  Google Scholar 

  80. Tzeng J-I, Chen B-C, Chang H-M et al (2010) Involvement of phosphatidylcholine-phospholipase C and protein kinase C in peptidoglycan-induced nuclear factor-[kappa]B activation and cyclooxygenase-2 expression in RAW 264.7 macrophages. Pharmacol Res 61:162–166

    Article  PubMed  CAS  Google Scholar 

  81. Heller RA, Kronke M (1994) TNF receptor-mediated signaling pathways. J Cell Biol 126:5–9

    Article  PubMed  CAS  Google Scholar 

  82. Schutze S, Berkovic D, Tomsing O et al (1991) TNF-α induces rapid production of 1′, 2′-diacylglycerol by a phosphatidylcholine-specific PLC. J Exp Med 174:975–988

    Article  PubMed  CAS  Google Scholar 

  83. Schutze S, Machleidt T, Kronke M (1994) The role of diacylglycerol and ceramide in TNF-α and IL-1 signal transduction. J Leukoc Biol 56:533–541

    PubMed  CAS  Google Scholar 

  84. Meng A, Luberto C, Meier P et al (2004) Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res 292:385–392

    Article  PubMed  CAS  Google Scholar 

  85. Li Z, Hailemariam TK, Zhou H et al (2007) Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochim Biophys Acta 1771:1186–1194

    PubMed  CAS  Google Scholar 

  86. Lee W-K, Torchalski B, Thevenod F (2007) Cadmium-induced ceramide formation triggers calpain-dependent apoptosis in cultured kidney proximal tubule cells. Am J Physiol—Cell Physiol 293:C839–C847

    Article  PubMed  CAS  Google Scholar 

  87. Lee WK, Torchalski B, Kohistani N et al (2011) ABCB1 protects kidney proximal tubule cells against cadmium-induced apoptosis: roles of cadmium and ceramide transport. Toxicol Sci 121:343–356

    Article  PubMed  CAS  Google Scholar 

  88. Li H, Zhang L, Yin D et al (2010) Targeting phosphatidylcholine-specific phospholipase C for atherogenesis therapy. Trends Cardiovasc Med 20:172–176

    Article  PubMed  CAS  Google Scholar 

  89. Zhou D, Lauderback CM, Yu T et al (2001) D609 inhibits ionizing radiation-induced oxidative damage by acting as a potent antioxidant. J Pharmacol Exp Ther 298:103–109

    PubMed  CAS  Google Scholar 

  90. Ansari MA, Joshi G, Huang Q et al (2006) In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders. Free Radic Biol Med 41:1694–1703

    Article  PubMed  CAS  Google Scholar 

  91. Opii WO, Sultana R, Abdul HM et al (2007) Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)–2′, 3′-dideoxycytidine (ddC): relevance to HIV-dementia. Exp Neurol 204:29–38

    Article  PubMed  CAS  Google Scholar 

  92. Joshi G, Sultana R, Perluigi M et al (2005) In vivo protection of synaptosomes from oxidative stress mediated by Fe2+/H2O2 or 2, 2-azobis-(2-amidinopropane) dihydrochloride by the glutathione mimetic tricyclodecan-9-yl-xanthogenate. Free Radic Biol Med 38:1023–1031

    Article  PubMed  CAS  Google Scholar 

  93. Abdul HM, Butterfield DA (2005) Protection against amyloid β-peptide (1–42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: implications for Alzheimer’s disease. Biochim Biophys Acta 1741:140–148

    Google Scholar 

  94. Lauderback CM, Drake J, Zhou D et al (2003) Derivatives of xanthic acid are novel antioxidants: application to synaptosomes. Free Radic Res 37:355–365

    Article  PubMed  CAS  Google Scholar 

  95. Giron-Calle J, Srivatsa K, Forman HJ (2002) Priming of alveolar macrophage respiratory burst by H2O2 is prevented by phosphatidylcholine-specific phospholipase C inhibitor tricyclodecan-9-yl-xanthate (D609). J Pharmacol Exp Ther 301:87–94

    Article  PubMed  CAS  Google Scholar 

  96. Kiss Z, Tomono M (1995) Compound D609 inhibits phorbol ester-stimulated phospholipase D activity and phospholipase C-mediated phosphatidylethanolamine hydrolysis. Biochim Biophys Acta 1259:105–108

    PubMed  Google Scholar 

  97. Su H-C, Ma C-T, Lin C-F et al (2011) The acid sphingomyelinase inhibitors block interferon-[alpha]-induced serotonin uptake via a COX-2/Akt/ERK/STAT-dependent pathway in T cells. Int Immunopharmacol 11:1823–1831

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by NIH R01 NS063959 and AHA 11GRNT7360066 grants to Adibhatla.

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Authors and Affiliations

  1. Department of Neurological Surgery, H4-330, Clinical Science Center, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI, 53792-3232, USA

    Rao Muralikrishna Adibhatla, J. F. Hatcher & A. Gusain

  2. Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Rao Muralikrishna Adibhatla

  3. Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Rao Muralikrishna Adibhatla

  4. William S. Middleton Veterans Affairs Hospital, Madison, WI, USA

    Rao Muralikrishna Adibhatla

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  1. Rao Muralikrishna Adibhatla
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Correspondence to Rao Muralikrishna Adibhatla.

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Adibhatla, R.M., Hatcher, J.F. & Gusain, A. Tricyclodecan-9-yl-Xanthogenate (D609) Mechanism of Actions: A Mini-Review of Literature. Neurochem Res 37, 671–679 (2012). https://doi.org/10.1007/s11064-011-0659-z

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