thromboxane-a2 and Neoplasms

Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A

Topics: Blood Platelets; Humans; Neoplasms; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, G-Protein-Coupled; Thromboxane A2

Platelets play a central role in inflammation through their direct interaction with other cell types, such as leucocytes and endothelial cells, and by the release of many factors, that is, lipids [such as thromboxane (TX)A2 ] and proteins (a wide number of angiogenic and growth factors) stored in α-granules, and adenosine diphosphate (ADP), stored in dense granules. These platelet actions trigger autocrine and paracrine activation processes that lead to leucocyte recruitment into different tissues and phenotypic changes in stromal cells which contribute to the development of different disease states, such as atherosclerosis and atherothrombosis, intestinal inflammation and cancer. The signals induced by platelets may cause pro-inflammatory and malignant phenotypes in other cells through the persistent induction of aberrant expression of cyclooxygenase (COX)-2 and increased generation of prostanoids, mainly prostaglandin (PG)E2 . In addition to cardiovascular disease, enhanced platelet activation has been detected in inflammatory disease and intestinal tumourigenesis. Moreover, the results of clinical studies have shown that the antiplatelet drug aspirin reduces the incidence of vascular events and colorectal cancer. All these pieces of evidence support the notion that colorectal cancer and atherothrombosis may share a common mechanism of disease, that is, platelet activation in response to epithelial (in tumourigenesis) and endothelial (in tumourigenesis and atherothrombosis) injury. Extensive translational medicine research is necessary to obtain a definitive mechanistic demonstration of the platelet-mediated hypothesis of colon tumourigenesis. The results of these studies will be fundamental to support the clinical decision to recommend the use of low-dose aspirin, and possibly other antiplatelet agents, in primary prevention, that is, even for individuals at low cardiovascular risk.

Topics: Animals; Aspirin; Blood Platelets; Cardiovascular Diseases; Colorectal Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Endothelial Cells; Humans; Inflammation; Leukocytes; Neoplasms; Platelet Activation; Platelet Aggregation Inhibitors; Stromal Cells; Thromboxane A2; Up-Regulation

Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients.

Topics: Dinoprost; Dinoprostone; Epigenesis, Genetic; Epoprostenol; Gene Silencing; Humans; Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Signal Transduction; Thromboxane A2

Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A(2) synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A(2) is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA(2)S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA(2) as a downstream metabolite of the COX-2-derived PGH(2). Several studies suggest potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA(2)S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA(2)S and TP in cancer progression and metastasis.

Topics: Amino Acid Sequence; Animals; Cell Movement; Disease Progression; Humans; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Receptors, Thromboxane; Signal Transduction; Thromboxane A2; Thromboxane-A Synthase

Eicosanoids and the enzymes responsible for their generation in living systems are involved in the mediation of multiple physiological and pathophysiological responses. These bioactive metabolites are part of complex cascades that initiate and perpetuate several disease processes such as atherosclerosis, arthritis, neurodegenerative conditions, and cancer. The intricate role played by each of these metabolites in the initiation, progression, and metastasis of solid tumors has been a subject of intense research in the scientific community. This review summarizes some of the key aspects of eicasonoids and the associated enzymes, and the pathways they mediate in promoting tumor progression and metastasis.

Topics: Animals; Arachidonic Acids; Blood Platelets; Dinoprostone; Disease Progression; Eicosanoids; Epoprostenol; Humans; Lipoxygenase; Metabolic Networks and Pathways; Neoplasm Metastasis; Neoplasms; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecox

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Digestive System Diseases; Disease Models, Animal; Drug Delivery Systems; Drug Design; Fever; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Inflammation; Isoenzymes; Neoplasms; Neurodegenerative Diseases; Pain; Prostaglandins; Signal Transduction; Stroke; Thromboxane A2

In response to various growth factors, hormones or cytokines, arachidonic acid can be mobilized from phospholipids pools and converted to bioactive eicosanoids through cyclooxygenase (COX), lipoxygenase (LOX) or P-450 epoxygenase pathway. The COX pathway generates five major prostanoids (prostaglandin D(2), prostaglandin E(2), prostaglandin F(2)alpha, prostaglandin I(2) and thromboxane A(2)) that play important roles in diverse biological processes. Studies suggest that different prostanoids and their own synthase can play distinct roles in tumor progression and cancer metastasis. COX-2 and PGE(2) synthase have been most well documented in the regulation of various aspects of tumor progression and metastasis. PGE(2), for example, can stimulate angiogenesis or other signaling pathways by binding to its receptors termed EPs. Therefore, targeting downstream prostanoids may provide a new avenue to impede tumor progression. In this review, aberrant expression and functions of several prostanoid synthetic enzymes in cancer will be discussed. The possible regulation of tumor progression by prostaglandins and their receptors will also be discussed.

Topics: Animals; Dinoprostone; Disease Progression; Humans; Neoplasms; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, Prostaglandin; Thromboxane A2

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

Topics: Animals; Atherosclerosis; Blood Platelets; Diabetic Retinopathy; Drug Design; Enzyme Inhibitors; Humans; Myocardial Infarction; Neoplasms; Neovascularization, Pathologic; Platelet Aggregation; Prostaglandins; Receptors, Thromboxane A2, Prostaglandin H2; Structure-Activity Relationship; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Angiogenesis is required for multistage carcinogenesis. The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. COX-2 expression occurs in a wide range of preneoplastic and malignant conditions; and the enzyme has been localized to the neoplastic cells, endothelial cells, immune cells, and stromal fibroblasts within tumors. The proangiogenic effects of COX-2 are mediated primarily by three products of arachidonic metabolism: thromboxane A(2) (TXA(2)), prostaglandin E(2) (PGE(2)), and prostaglandin I(2) (PGI(2)). Downstream proangiogenic actions of these eicosanoid products include: (1) production of vascular endothelial growth factor; (2) promotion of vascular sprouting, migration, and tube formation; (3) enhanced endothelial cell survival via Bcl-2 expression and Akt signaling; (4) induction of matrix metalloproteinases; (5) activation of epidermal growth factor receptor-mediated angiogenesis; and (6) suppression of interleukin-12 production. Selective inhibition of COX-2 activity has been shown to suppress angiogenesis in vitro and in vivo. Because these agents are safe and well tolerated, selective COX-2 inhibitors could have clinical utility as antiangiogenic agents for cancer prevention, as well as for intervention in established disease alone or in combination with chemotherapy, radiation, and biological therapies.

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Celecoxib; Cell Movement; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Epidermal Growth Factor; Epoprostenol; Humans; Interleukin-12; Isoenzymes; Lactones; Matrix Metalloproteinases; Membrane Proteins; Neoplasms; Neovascularization, Pathologic; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Signal Transduction; Sulfonamides; Sulfones; Thromboxane A2; Vascular Endothelial Growth Factor A

It is clear that COX-2 plays an important role in tumor and endothelial cell biology. Increased expression of COX-2 occurs in multiple cells within the tumor microenvironment that can impact on angiogenesis. COX-2 appears to: (a) play a key role in the release and activity of proangiogenic proteins; (b) result in the production of eicosanoid products TXA2, PGI2, PGE2 that directly stimulate endothelial cell migration and angiogenesis in vivo, and (c) result in enhanced tumor cell, and possibly, vascular endothelial cell survival by upregulation of the antiapoptotic proteins Bcl-2 and/or activation of PI3K-Akt. Selective pharmacologic inhibition of COX-2 represents a viable therapeutic option for the treatment of malignancies. Agents that selectively inhibit COX-2 appear to be safe, and well tolerated suggesting that chronic treatment for angiogenesis inhibition is feasible [107-110]. Because these agents inhibit angiogenesis, they should have at least additive benefit in combination with standard chemotherapy [111] and radiation therapy [24, 112]. In preclinical models, a selective inhibitor of COX-2 was shown to potentiate the beneficial antitumor effects of ionizing radiation with no increase in normal tissue cytotoxicity [113-115]. More recently, metronomic dosing regimens of standard chemotherapeutic agents without extended rest periods were shown to target the microvasculature in experimental animal models and result in significant antitumor activity [116-118]. This antiangiogenic chemotherapy regimen could be enhanced by the concurrent administration of an angiogenesis inhibitor [116-119]. Trials that will evaluate continuous low dose cyclophosphamide in combination with celecoxib are underway in patients with metastatic renal cancer, and non-Hodgkin's lymphoma [120]. Given the safety and tolerability of the selective COX-2 inhibitors, and the potent antiangiogenic properties of these agents, the combination of antiangiogenic chemotherapy with a COX-2 inhibitor warrants clinical evaluation [118, 121, 122]. The effects of selective COX-2 inhibitors on angiogenesis may also be due, in part, to COX-independent mechanisms [123-125]. Several reports have confirmed COX-independent effects of celecoxib, at relatively high concentrations (50 microM), where apoptosis is stimulated in cells that lack both COX-1 and COX-2 [126]. More recently, Song et al. [127] described structural modifications to celecoxib that revealed no association between the COX-2 inhib

Topics: Animals; Apoptosis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Endothelial Growth Factors; Humans; Intercellular Signaling Peptides and Proteins; Isoenzymes; Lymphokines; Membrane Proteins; Neoplasms; Neovascularization, Pathologic; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Epoprostenol; Humans; Kidney; Neoplasms; Shock; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vascular Resistance

Topics: Animals; Arachidonic Acids; Blood Coagulation Disorders; Fibrinolysis; Hemostasis; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Thrombocytopenia; Thromboxane A2

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cathepsin B; Cathepsins; Cell Line; Cell Membrane; Epoprostenol; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Prostaglandins; Pyrazoles; Pyrazolones; Rats; Serotonin; Thromboxane A2

Topics: Animals; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Cyclooxygenase Inhibitors; DNA; Epoprostenol; Female; Hematopoietic Stem Cells; Humans; Kidney; Male; Mutagens; Neoplasm Metastasis; Neoplasms; Oxidation-Reduction; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Skin; Tetradecanoylphorbol Acetate; Thromboxane A2

A broad body of evidence indicates the involvement of P450 TxA2 (thromboxane A2 synthetase) in tumor metastasis formation. A distinct function of the enzyme in this multistep process, however, is still unknown. Therefore the effect of TxA2 (thromboxane A2) on tumor cell adhesion to the basement membrane, a key event in metastasis formation, was investigated.. A wide variety of compounds designed in our work group and identified as P450 TxA2 inhibitors were applied to several P450 TxA2-positive tumor cell lines to test their influence on tumor cell adhesion. For this purpose an in-vitro basement membrane adhesion model with the matrix gel preparation Matrigel was used.. Most of the P450 TxA2 inhibitors tested had no effect on cell adhesion. Although two compounds significantly reduced tumor cell adhesion in a concentration-dependent manner, this was not related to P450 TxA2 inhibition.. These data indicate that TxA2 might not be involved in the attachment of tumor cell lines to the basement membrane.

Topics: Basement Membrane; Cell Adhesion; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Neoplasms; Thromboxane A2; Thromboxane-A Synthase; Tumor Cells, Cultured; U937 Cells

Recently, addition of gamma linolenic acid (GLA) which is a precursor of prostaglandin E1 (PGE1) to cell cultures, has been shown to inhibit growth of various carcinoma cells (1,2,3,4). These findings are consistent with Horrobin's proposal that some of the metabolic abnormalities of malignant cells may be due to deficiencies of certain prostanoids. To determine whether the observed effects of GLA are in fact mediated by increasing levels of its metabolites, this study investigated the influence of various inhibitors and stimulants of prostaglandin (PG) synthesis on the effects of GLA on carcinoma cells in vitro. Most of the agents used (aspirin, imidazole, lithium carbonate and ascorbic acid) produced results consistent with the idea that elevation of levels of thromboxane A2 (TxA2) and/or PGE1 may be important as regards the actions of GLA. In sharp contrast was the result obtained with indomethacin. This drug, which could be expected to block conversion of GLA to PGE1 and therefore protect cells against the effects of GLA, actually exaggerated the effects of this fatty acid, thereby causing cell death and desquamation.

Topics: Alprostadil; Aspirin; Cell Division; Cell Line; Cell Survival; gamma-Linolenic Acid; Humans; Imidazoles; Indomethacin; Linolenic Acids; Neoplasms; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxanes

Topics: Anti-Inflammatory Agents; Arachidonic Acids; Epoprostenol; Gastrointestinal Diseases; Humans; Kidney Diseases; Lung Diseases; Neoplasms; Prostaglandins; SRS-A; Thromboxane A2; Thromboxanes; Vascular Diseases

A failure of thromboxane (TX) A2 synthesis may be a factor in cancer. Such a loss could explain the susceptibility to mutation, the excess prostaglandin production, the glycolytic mode of metabolism and the deranged calcium pumping characteristic of cancers. Ionising radiation and phorbols both have actions similar to inhibitors of TXA2 synthesis whereas colchicine and oxygen have actions consistent with stimulation of TXA2 synthesis. The concept accounts logically for hitherto unexplained features of cancer and suggests new strategies for the prevention and treatment of cancer.

Topics: Animals; DNA; Humans; Mutation; Neoplasms; Prostaglandins; Psoriasis; Radiation Injuries; Thromboxane A2; Thromboxanes; Ultraviolet Rays; Xeroderma Pigmentosum