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Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression

Published online by Cambridge University Press:  15 October 2007

Mandi Murph  and
Gordon B. Mills
Mandi Murph*
Affiliation:
Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Gordon B. Mills
Affiliation:
Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
*
*Corresponding author: Mandi Murph, Department of Systems Biology, Unit 950, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel: +1 713 563 4225; Fax: +1 713 563 4235; E-mail: mmmurph@mdanderson.org
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Abstract

The bioactive lipids lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), the enzymes that generate and degrade them, and the receptors that receive their signals are all potential therapeutic targets in cancer. LPA and S1P signalling pathways can modulate a range of cellular processes that contribute to tumourigenesis, such as proliferation and motility, and components of the signalling pathways often show aberrant expression and altered activity upon malignant transformation. This article reviews LPA- and S1P-mediated activities that might contribute to the aetiology of cancer, and examines the potential of the many antagonists that have been developed to inhibit LPA and S1P signalling pathways. In addition, the outcomes of various clinical trials using LPA- and S1P-associated targets in cancer and other diseases are described, and future directions are discussed.

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Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 9 , Issue 28 , October 2007 , pp. 1 - 18
Copyright
Copyright © Cambridge University Press 2007

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References

References

1Lee, H., Goetzl, E.J. and An, S. (2000) Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing. Am J Physiol Cell Physiol 278, C612-618CrossRefGoogle ScholarPubMed
2Chemin, J. et al. (2005) Lysophosphatidic acid-operated K+ channels. J Biol Chem 280, 4415-4421CrossRefGoogle ScholarPubMed
3Gaits, F. et al. (1997) Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis. FEBS Lett 410, 54-58CrossRefGoogle ScholarPubMed
4Pages, C. et al. (2001) Lysophosphatidic acid synthesis and release(1). Prostaglandins 64, 1-10CrossRefGoogle Scholar
5Ren, J. et al. (2006) Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res 66, 3006-3014CrossRefGoogle ScholarPubMed
6Baker, D.L. et al. (2001) Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry. Anal Biochem 292, 287-295CrossRefGoogle ScholarPubMed
7Ye, X. et al. (2005) LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104-108CrossRefGoogle ScholarPubMed
8Tokumura, A. et al. (2002) Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy. Biol Reprod 67, 1386-1392CrossRefGoogle ScholarPubMed
9Mills, G.B. and Moolenaar, W.H. (2003) The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3, 582-591CrossRefGoogle ScholarPubMed
10Tanyi, J.L. et al. (2003) The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. Cancer Res 63, 1073-1082Google ScholarPubMed
11Xu, Y. et al. (1998) Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. Jama 280, 719-723CrossRefGoogle ScholarPubMed
12Yoon, H.R., Kim, H. and Cho, S.H. (2003) Quantitative analysis of acyl-lysophosphatidic acid in plasma using negative ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 788, 85-92CrossRefGoogle ScholarPubMed
13Sasagawa, T. et al. (1999) Abnormal serum lysophospholipids in multiple myeloma patients. Lipids 34, 17-21CrossRefGoogle ScholarPubMed
14Xu, Y. et al. (1995) Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res 1, 1223-1232Google ScholarPubMed
15Xie, Y., Gibbs, T.C. and Meier, K.E. (2002) Lysophosphatidic acid as an autocrine and paracrine mediator. Biochim Biophys Acta 1582, 270-281CrossRefGoogle ScholarPubMed
16Baker, D.L. et al. (2002) Plasma lysophosphatidic acid concentration and ovarian cancer. Jama 287, 3081-3082CrossRefGoogle ScholarPubMed
17Westermann, A.M. et al. (1998) Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol 9, 437-442CrossRefGoogle ScholarPubMed
18Stracke, M.L. et al. (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267, 2524-2529CrossRefGoogle ScholarPubMed
19Umezu-Goto, M. et al. (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158, 227-233CrossRefGoogle ScholarPubMed
20Clair, T. et al. (2003) Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res 63, 5446-5453Google ScholarPubMed
21Nam, S.W. et al. (2000) Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene 19, 241-247CrossRefGoogle ScholarPubMed
22Nam, S.W. et al. (2001) Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Cancer Res 61, 6938-6944Google ScholarPubMed
23Tanaka, M. et al. (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem 281, 25822-25830CrossRefGoogle ScholarPubMed
24van Meeteren, L.A. et al. (2006) Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 26, 5015-5022CrossRefGoogle ScholarPubMed
25Nakamura, K. et al. (2007) Measurement of lysophospholipase D/autotaxin activity in human serum samples. Clin Biochem 40, 274-277CrossRefGoogle ScholarPubMed
26Tsuda, S. et al. (2006) Cyclic phosphatidic acid is produced by autotaxin in blood. J Biol Chem 281, 26081-26088CrossRefGoogle ScholarPubMed
27van Meeteren, L.A. et al. (2005) Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J Biol Chem 280, 21155-21161CrossRefGoogle ScholarPubMed
28Zhang, G. et al. (1999) Expression of autotaxin mRNA in human hepatocellular carcinoma. Chin Med J (Engl) 112, 330-332Google ScholarPubMed
29Yang, S.Y. et al. (2002) Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Clin Exp Metastasis 19, 603-608CrossRefGoogle ScholarPubMed
30Yang, Y. et al. (1999) Autotaxin expression in non-small-cell lung cancer. Am J Respir Cell Mol Biol 21, 216-222CrossRefGoogle ScholarPubMed
31Stassar, M.J. et al. (2001) Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer 85, 1372-1382CrossRefGoogle ScholarPubMed
32Kehlen, A. et al. (2004) Expression, regulation and function of autotaxin in thyroid carcinomas. Int J Cancer 109, 833-838CrossRefGoogle ScholarPubMed
33Kishi, Y. et al. (2006) Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem 281, 17492-17500CrossRefGoogle ScholarPubMed
34Baumforth, K.R. et al. (2005) Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells. Blood 106, 2138-2146CrossRefGoogle ScholarPubMed
35Mizugishi, K. et al. (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25, 11113-11121CrossRefGoogle ScholarPubMed
36Lee, O.H. et al. (1999) Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun 264, 743-750CrossRefGoogle ScholarPubMed
37Spiegel, S. and Milstien, S. (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4, 397-407CrossRefGoogle ScholarPubMed
38Ancellin, N. et al. (2002) Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem 277, 6667-6675CrossRefGoogle ScholarPubMed
39Johnson, K.R. et al. (2002) PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J Biol Chem 277, 35257-35262CrossRefGoogle Scholar
40Anelli, V. et al. (2005) Extracellular release of newly synthesized sphingosine-1-phosphate by cerebellar granule cells and astrocytes. J Neurochem 92, 1204-1215CrossRefGoogle ScholarPubMed
41Hanel, P., Andreani, P. and Graler, M.H. (2007) Erythrocytes store and release sphingosine 1-phosphate in blood. Faseb J 21, 1202-1209CrossRefGoogle ScholarPubMed
42English, D. et al. (2000) Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. Faseb J 14, 2255-2265CrossRefGoogle ScholarPubMed
43Hong, G., Baudhuin, L.M. and Xu, Y. (1999) Sphingosine-1-phosphate modulates growth and adhesion of ovarian cancer cells. FEBS Lett 460, 513-518CrossRefGoogle ScholarPubMed
44von Otte, S. et al. (2006) Follicular fluid high density lipoprotein-associated sphingosine 1-phosphate is a novel mediator of ovarian angiogenesis. J Biol Chem 281, 5398-5405CrossRefGoogle ScholarPubMed
45Kono, M. et al. (2004) The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem 279, 29367-29373CrossRefGoogle ScholarPubMed
46Visentin, B. et al. (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225-238CrossRefGoogle ScholarPubMed
47Chae, S.S. et al. (2004) Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest 114, 1082-1089CrossRefGoogle ScholarPubMed
48Maceyka, M. et al. (2005) SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 280, 37118-37129CrossRefGoogle ScholarPubMed
49Xia, P. et al. (2000) An oncogenic role of sphingosine kinase. Curr Biol 10, 1527-1530CrossRefGoogle ScholarPubMed
50Johnson, K.R. et al. (2005) Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem 53, 1159-1166CrossRefGoogle ScholarPubMed
51Van Brocklyn, J.R. et al. (2005) Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 64, 695-705CrossRefGoogle ScholarPubMed
52Kohno, M. et al. (2006) Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol 26, 7211-7223CrossRefGoogle ScholarPubMed
53Bektas, M. et al. (2005) Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene 24, 178-187CrossRefGoogle ScholarPubMed
54Pchejetski, D. et al. (2005) Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res 65, 11667-11675CrossRefGoogle ScholarPubMed
55Akao, Y. et al. (2006) High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun 342, 1284-1290CrossRefGoogle ScholarPubMed
56Balthasar, S. et al. (2006) Sphingosine 1-phosphate receptor expression profile and regulation of migration in human thyroid cancer cells. Biochem J 398, 547-556CrossRefGoogle ScholarPubMed
57Yamashita, H. et al. (2006) Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells: differential regulation on the migration and proliferation. J Surg Res 130, 80-87CrossRefGoogle ScholarPubMed
58Nakamoto, T. et al. (2005) Expression of the endothelial cell differentiation gene 7 (EDG-7), a lysophosphatidic acid receptor, in ovarian tumor. J Obstet Gynaecol Res 31, 344-351CrossRefGoogle ScholarPubMed
59Yun, C.C. et al. (2005) LPA2 receptor mediates mitogenic signals in human colon cancer cells. Am J Physiol Cell Physiol 289, C2-11CrossRefGoogle ScholarPubMed
60Shida, D. et al. (2004) Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer. Lab Invest 84, 1352-1362CrossRefGoogle ScholarPubMed
61Kitayama, J. et al. (2004) Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma. Breast Cancer Res 6, R640-646CrossRefGoogle ScholarPubMed
62Yamashita, H. et al. (2006) Differential expression of lysophosphatidic acid receptor-2 in intestinal and diffuse type gastric cancer. J Surg Oncol 93, 30-35CrossRefGoogle ScholarPubMed
63Schlyer, S. and Horuk, R. (2006) I want a new drug: G-protein-coupled receptors in drug development. Drug Discov Today 11, 481-493CrossRefGoogle Scholar
64LaMontagne, K. et al. (2006) Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res 66, 221-231CrossRefGoogle ScholarPubMed
65Brinkmann, V. et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277, 21453-21457CrossRefGoogle ScholarPubMed
66Brinkmann, V., Cyster, J.G. and Hla, T. (2004) FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4, 1019-1025CrossRefGoogle ScholarPubMed
67Luo, Z.J. et al. (1999) Analysis of the mode of action of a novel immunosuppressant FTY720 in mice. Immunopharmacology 41, 199-207CrossRefGoogle ScholarPubMed
68Kahan, B.D. et al. (2003) Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 76, 1079-1084CrossRefGoogle ScholarPubMed
69Tedesco-Silva, H. et al. (2005) FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 79, 1553-1560CrossRefGoogle ScholarPubMed
70Mulgaonkar, S. et al. (2006) FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study. Am J Transplant 6, 1848-1857CrossRefGoogle ScholarPubMed
71Tedesco Silva, H. Jr. et al. , (2006) Immunotherapy for De Novo renal transplantation: what's in the pipeline? Drugs 66, 1665-1684CrossRefGoogle Scholar
72Budde, K. et al. (2006) FTY720 (fingolimod) in renal transplantation. Clin Transplant 20 Suppl 17, 17-24CrossRefGoogle Scholar
73Schmid, G. et al. (2007) The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1. J Cell Biochem 101, 259-270CrossRefGoogle ScholarPubMed
74Young, N. and Van Brocklyn, J.R. (2007) Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp Cell Res 313, 1615-1627CrossRefGoogle ScholarPubMed
75Park, K.S. et al. (2007) S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochem Biophys Res Commun 356, 239-244CrossRefGoogle ScholarPubMed
76Lepley, D. et al. (2005) The G protein-coupled receptor S1P2 regulates Rho/Rho kinase pathway to inhibit tumor cell migration. Cancer Res 65, 3788-3795CrossRefGoogle Scholar
77Inoki, I. et al. (2006) Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. Biochem Biophys Res Commun 346, 293-300CrossRefGoogle ScholarPubMed
78Boucharaba, A. et al. (2006) The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proc Natl Acad Sci U S A 103, 9643-9648CrossRefGoogle ScholarPubMed
79Stadler, C.R. et al. (2006) FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression. Cell Signal 18, 783-794CrossRefGoogle ScholarPubMed
80Yamada, T. et al. (2004) Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1. J Biol Chem 279, 6595-6605CrossRefGoogle ScholarPubMed
81Schulte, K.M. et al. (2001) Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer. Int J Cancer 92, 249-2563.0.CO;2-D>CrossRefGoogle ScholarPubMed
82Lee, Z. et al. (2006) Lysophosphatidic acid is a major regulator of growth-regulated oncogene alpha in ovarian cancer. Cancer Res 66, 2740-2748CrossRefGoogle Scholar
83Fujiwara, Y. et al. (2005) Identification of residues responsible for ligand recognition and regioisomeric selectivity of lysophosphatidic acid receptors expressed in mammalian cells. J Biol Chem 280, 35038-35050CrossRefGoogle ScholarPubMed
84Hama, K. et al. (2006) Lysophosphatidic receptor, LPA3, is positively and negatively regulated by progesterone and estrogen in the mouse uterus. Life Sci 79, 1736-1740CrossRefGoogle ScholarPubMed
85Daub, H. et al. (1996) Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557-560CrossRefGoogle ScholarPubMed
86Kim, J.H. et al. (2000) Sphingosine 1-phosphate activates Erk-1/-2 by transactivating epidermal growth factor receptor in rat-2 cells. IUBMB Life 50, 119-124Google ScholarPubMed
87Shida, D. et al. (2005) Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells. Biochem Biophys Res Commun 327, 907-914CrossRefGoogle ScholarPubMed
88Baudhuin, L.M. et al. (2004) S1P3-mediated Akt activation and cross-talk with platelet-derived growth factor receptor (PDGFR). Faseb J 18, 341-343CrossRefGoogle ScholarPubMed
89Endo, A. et al. (2002) Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII. J Biol Chem 277, 23747-23754CrossRefGoogle ScholarPubMed
90Sukocheva, O. et al. (2006) Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J Cell Biol 173, 301-310CrossRefGoogle ScholarPubMed
91So, J. et al. (2005) LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2). Gynecol Oncol 97, 870-878CrossRefGoogle ScholarPubMed
92Wang, L. et al. (2003) Involvement of phospholipase D2 in lysophosphatidate-induced transactivation of platelet-derived growth factor receptor-beta in human bronchial epithelial cells. J Biol Chem 278, 39931-39940CrossRefGoogle ScholarPubMed
93Zaslavsky, A. et al. (2006) Homo- and hetero-dimerization of LPA/S1P receptors, OGR1 and GPR4. Biochim Biophys Acta 1761, 1200-1212CrossRefGoogle ScholarPubMed
94Kobayashi, T. et al. (1999) Existence of a bioactive lipid, cyclic phosphatidic acid, bound to human serum albumin. Life Sci 65, 2185-2191CrossRefGoogle ScholarPubMed
95Murakami-Murofushi, K. et al. (2002) Biological functions of a novel lipid mediator, cyclic phosphatidic acid. Biochim Biophys Acta 1582, 1-7CrossRefGoogle ScholarPubMed
96Baker, D.L. et al. (2006) Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. J Biol Chem 281, 22786-22793CrossRefGoogle ScholarPubMed
97Gududuru, V. et al. (2006) Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors. Bioorg Med Chem Lett 16, 451-456CrossRefGoogle ScholarPubMed
98Clair, T. et al. (2005) L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin. Lipids Health Dis 4, 5CrossRefGoogle ScholarPubMed
99French, K.J. et al. (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63, 5962-5969Google ScholarPubMed
100French, K.J. et al. (2006) Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther 318, 596-603CrossRefGoogle ScholarPubMed
101Igarashi, Y. et al. (1989) Effect of chemically well-defined sphingosine and its N-methyl derivatives on protein kinase C and src kinase activities. Biochemistry 28, 6796-6800CrossRefGoogle ScholarPubMed
102Schwartz, G.K. et al. (1997) A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 3, 537-543Google ScholarPubMed
103Gamble, J.R. et al. (2006) Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int J Cancer 118, 2412-2420CrossRefGoogle ScholarPubMed
104de Souza, P.L. et al. (2006) Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer. Cancer Chemother Pharmacol 58, 427-433CrossRefGoogle ScholarPubMed
105Choueiri, T.K. et al. (2006) Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann Oncol 17, 860-865CrossRefGoogle ScholarPubMed
106Hanel, P., Andreani, P. and Graler, M.H. (2007) Erythrocytes store and release sphingosine 1-phosphate in blood. Faseb J 21, 1202-1209CrossRefGoogle ScholarPubMed
107Cuvillier, O. (2007) Sphingosine kinase-1 – a potential therapeutic target in cancer. Anticancer Drugs 18, 105-110CrossRefGoogle ScholarPubMed
108Davis, M.D. et al. (2005) Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem 280, 9833-9841CrossRefGoogle ScholarPubMed
109Durgam, G.G. et al. (2006) Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands. Bioorg Med Chem Lett 16, 633-640CrossRefGoogle ScholarPubMed
110Durgam, G.G. et al. (2005) Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activators of PPARgamma, and inhibitors of autotaxin. J Med Chem 48, 4919-4930CrossRefGoogle ScholarPubMed
111Fischer, D.J. et al. (2001) Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Mol Pharmacol 60, 776-784Google ScholarPubMed
112Foss, F.W. Jr. et al. (2007) Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem 15, 663-677CrossRefGoogle ScholarPubMed
113Heasley, B.H. et al. (2004) Initial structure-activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist. Bioorg Med Chem Lett 14, 2735-2740CrossRefGoogle ScholarPubMed
114Kono, K. et al. (2000) F-12509A, a new sphingosine kinase inhibitor, produced by a discomycete. J Antibiot (Tokyo) 53, 459-466CrossRefGoogle ScholarPubMed
115Kono, K. et al. (2000) Characterization of B-5354c, a new sphingosine kinase inhibitor, produced by a marine bacterium. J Antibiot (Tokyo) 53, 759-764CrossRefGoogle ScholarPubMed
116Kono, K. et al. (2001) S-15183a and b, new sphingosine kinase inhibitors, produced by a fungus. J Antibiot (Tokyo) 54, 415-420CrossRefGoogle Scholar
117Lee, S. and Lynch, K.R. (2005) Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA). Biochem J 391, 317-323CrossRefGoogle ScholarPubMed
118Liliom, K. et al. (2006) Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: inhibition of LPA GPCR and activation of PPARs. Biochim Biophys Acta 1761, 1506-1514CrossRefGoogle ScholarPubMed
119Ohta, H. et al. (2003) Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol 64, 994-1005CrossRefGoogle ScholarPubMed
120Okusa, M.D. et al. (2003) Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 285, F565-574CrossRefGoogle ScholarPubMed
121Oo, M.L. et al. (2007) Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 (S1P1) agonists induce ubiquitinylation and proteosomal degradation of the receptor. J Biol ChemCrossRefGoogle ScholarPubMed
122Osada, M. et al. (2002) Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun 299, 483-487CrossRefGoogle ScholarPubMed
123Sanna, M.G. et al. (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2, 434-441CrossRefGoogle ScholarPubMed
124Smyth, S.S. et al. (2003) Lipid phosphate phosphatases regulate lysophosphatidic acid production and signaling in platelets: studies using chemical inhibitors of lipid phosphate phosphatase activity. J Biol Chem 278, 43214-43223CrossRefGoogle ScholarPubMed
125Tamaruya, Y. et al. (2004) Identifying specific conformations by using a carbohydrate scaffold: discovery of subtype-selective LPA-receptor agonists and an antagonist. Angew Chem Int Ed Engl 43, 2834-2837CrossRefGoogle Scholar
126Virag, T. et al. (2003) Fatty alcohol phosphates are subtype-selective agonists and antagonists of lysophosphatidic acid receptors. Mol Pharmacol 63, 1032-1042CrossRefGoogle ScholarPubMed
127Xu, Y. et al. (2006) Phosphonothioate and fluoromethylene phosphonate analogues of cyclic phosphatidic acid: Novel antagonists of lysophosphatidic acid receptors. J Med Chem 49, 5309-5315CrossRefGoogle ScholarPubMed
128Yamamoto, T. et al. (2007) Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists. Bioorg Med Chem Lett 17, 3736-3740CrossRefGoogle ScholarPubMed
129Nakamura, T. et al. (2007) Synthesis and SAR studies of a novel class of S1P1 receptor antagonists. Bioorg Med Chem 15, 3548-3564CrossRefGoogle ScholarPubMed
130Koide, Y. et al. (2007) Pharmacophore-based design of sphingosine 1-phosphate-3 receptor antagonists that include a 3,4-dialkoxybenzophenone scaffold. J Med Chem 50, 442-454CrossRefGoogle ScholarPubMed
131Jiang, G. et al. (2007) α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action on LPA. Chem Med Chem 2, 679-690CrossRefGoogle ScholarPubMed
132Xu, Y. and Prestwich, G. (2002) Synthesis of chiral (α,α-Difluoroalkyl)phosphonate analogues of (Lyso)phosphatidic acid via hydrolytic kinetic resolution. Org Lett 4, 4021-4024CrossRefGoogle Scholar

Further reading, resources and contacts

Clinical trials can be accessed through the US National Institutes of Health website. The NCT numbers described throughout this review can be searched there. This is a service developed by the National Library of Medicine, which provides regularly updated information on clinical research:

http://www.clinicaltrials.govGoogle Scholar
http://www.avantilipids.comGoogle Scholar
http://www.echelon-inc.comGoogle Scholar