Carba Analogs of Cyclic Phosphatidic Acid Are Selective Inhibitors of Autotaxin and Cancer Cell Invasion and Metastasis

Baker, Daniel L.; Fujiwara, Yuko; Pigg, Kathryn R.; Tsukahara, Ryoko; Kobayashi, Susumu; Murofushi, Hiromu; Uchiyama, Ayako; Murakami‐Murofushi, Kimiko; Koh, Eunjin; Bandle, Russell W.; Byun, Hoe‐Sup; Bittman, Robert; Fan, Dominic; Murph, Mandi M.; Mills, Gordon B.; Tigyi, Gábor

doi:10.1074/jbc.m512486200

Cited by 150 publications

(185 citation statements)

References 48 publications

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“…Most of the studies on the mechanisms of LPA in ovarian cancer have been conducted in vitro. Only recently, animal studies showing a role for LPA and/or its receptors in the development of cancers in vivo have been published (5)(6)(7)(8)(9). We have recently provided the first direct evidence that LPA stimulates tumor metastasis in vivo, which is inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor, and by 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of the heat shock protein 90, which stabilizes hypoxia-inducible factor-1α (10,11).…”

Section: Introductionmentioning

confidence: 93%

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

Wang

Zhang

et al. 2009

Molecular Cancer Therapeutics

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We have already established human xenographic models for the effect of lysophosphatidic acid (LPA) on tumor metastasis in vivo. The purpose of this work is to establish a preclinical LPA effect model in immunocompetent mice. We first characterized the mouse epithelial ovarian cancer (EOC) cell line ID8 for its responsiveness to LPA in cell proliferation, migration, and invasion and compared these properties with those of human EOC. The signaling pathways related to cell migration were further investigated using pharmacologic and genetic approaches. The effects of LPA on the tumorigenesis of ID8 cells and mouse survival were then examined using two different mouse models (i.p. and orthotopic injections). LPA stimulated cell proliferation, migration, and invasion of mouse EOC ID8 cells in a manner closely resembling its activity in human EOC cells. The signaling pathways involved in LPAinduced cell migration in ID8 cells were also similar to those identified in human EOC cells. We have identified cyclooxygenase-1 and 15-lipoxygenase as two new signaling molecules involved in LPA-induced cell migration in both human and mouse EOC cells. In addition, LPA enhanced the tumorigenesis/metastasis of ID8 cell in vivo as assessed by increased tumor size, early onset of ascites formation, and reduced animal survival. We have established the first LPA-EOC preclinical model in immunocompetent mice. Because ID8 cells respond to LPA similar to human EOC cells, this model is very valuable in developing and testing therapeutic reagents targeting LPA in

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Section: Introductionmentioning

confidence: 93%

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

Wang

Zhang

et al. 2009

Molecular Cancer Therapeutics

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“…Such a molecule has clear therapeutic potential to inhibiting the role of LPA in promoting tumor growth and metastasis. [51,52] …”

Section: Receptor Activation Assaysmentioning

confidence: 99%

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Jiang

Fujiwara

et al. 2007

ChemMedChem

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Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy-and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca 2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA 2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA 3 agonist. Most importantly, the α-bromomethylene and α-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA 4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

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“…Whole blood was sampled from the jugular vein and collected directly into anticoagulant, mixed, centrifuged, and plasma transferred to glass tubes containing acidified solvents for extraction of HA130 and LPA. All animal experiments conformed to the recommendations of the "Guide for the Care and Use of Laboratory Animals" (Department of Health, Education, and Welfare publication number NIH 78- 23,1996) and were approved by the institutional Animal Care and Use Committee.…”

Section: Studies In Micementioning

confidence: 99%

“…Direct targeting of LPA receptors seems to be a less attractive strategy, since LPA acts on multiple receptors that show overlapping activities (2 and 6). Since the initial finding that ATX is subject to product inhibition by LPA and sphingosine 1-phosphate (S1P) (22), various synthetic phospho-and phosphonate lipids have been explored as ATX inhibitors (23)(24)(25)(26). However, such lipid inhibitors have the inherent danger of inadvertently activating downstream LPA/S1P receptors, thereby inducing the opposite of the intended effect.…”

mentioning

confidence: 99%

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Albers

Dong

Meeteren

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/ phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC 50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.A utotaxin (ATX or NPP2) is a secreted nucleotide pyrophosphatase/phosphodiesterase (NPP) originally isolated as an autocrine motility factor from melanoma cells (1). ATX, a ∼120 kDa glycoprotein, is unique amongst the NPPs in that it functions as a lysophospholipase D (lysoPLD) that converts extracellular lysophosphatidylcholine (LPC) into the lipid mediator lysophosphatidic acid (LPA; mono-acyl-sn-glycero-3-phosphate) (2-5). LPA acts on specific G protein-coupled receptors and thereby stimulates the migration, proliferation, and survival of many cell types (6 and 7) (Fig. 1). ATX is produced by various tissues and is the major LPA-producing enzyme in the circulation. Newly produced LPA is subject to degradation by membranebound lipid phosphate phosphatases (LPPs) (8 and 9). However, little is known about the dynamic regulation of steady-state LPA levels in vivo.ATX is essential for vascular development (10 and 11) and is found overexpressed in various human cancers (12). Forced overexpression of ATX or individual LPA receptors promotes tumor progression in mouse models (13-16), while LPA receptor deficiency protects from colon carcinogenesis (17). In addition to its role in cancer, ATX-LPA signaling has been implicated in lymphocyte homing and (chronic) inflammation (18), fibrotic diseases (19 and 20), and thrombosis (21). Therefore, the ATX-LPA axis qualifies as an attractive target for therapies.Potent and selective ATX inhibitors are now needed as a starting point for the development of targeted anti-ATX/LPA therapy. Direct targeting of LPA receptors seems to be a less attractive strategy, since LPA acts on multiple receptors that show overlapping activities (2 and 6). Since the initial finding that ATX is subject to product inhibition by LPA and sphingosine 1-phosphate (S1P) (22), various synthetic phospho-and phosphonate lipids have been explored as ATX inhibitors (23-26). However, s...

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Carba Analogs of Cyclic Phosphatidic Acid Are Selective Inhibitors of Autotaxin and Cancer Cell Invasion and Metastasis

Cited by 150 publications

References 48 publications

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

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