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Results for “potential targets”

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PubMed2003

PPM1D is a potential target for 17q gain in neuroblastoma.

Neuroblastomas (NBs) show complex patterns of genetic abnormalities, which may include amplification of the MYCN gene, deletion of 1p, or a gain of DNA at 17q, the last being the most frequent observation in NB tumors. However, the specific genes and the molecular mechanisms responsible for development and progression of NB remain poorly understood. We investigated aberrations of DNA copy number in 25 NB cell lines using comparative genomic hybridization and identified a minimal common region of gain at 17q23. Although gain of distal 17q is the most powerful genetic predictor of adverse outcome currently available for patients with NB, thus far, no potential target genes have been reported for that region. Therefore, we defined the 17q23 amplicon in detail and determined expression levels of 15 genes located within the smallest region of overlap observed among our NB cell lines to identify the most likely target gene(s). Among them, seven (CLTC, VMP1, delta-tubulin, RPS6KB1, FLJ22087, APPBP2, and PPM1D) were consistently overexpressed through increases in regional copy number. Analysis of expression levels of those seven genes in 32 primary NB tumors revealed a significant correlation between higher expression and poorer clinical outcome only with respect to PPM1D. Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death. Taken together, our results indicate that PPM1D is the most likely target of the 17q23 gain/amplification in NB tumors and may have an important role in the pathogenesis of this disease.

Cell Death↗

PubMed2006

Adipocyte: a potential target for the treatment of atherosclerosis.

Obesity is an independent risk factor for coronary heart disease, whereas the underlying mechanisms have not been fully elucidated. Adipocytes may produce various adipokines with favorable and unfavorable cardiovascular effects. The dysregulated secretion of adipokines by adipocytes may contribute to obese associated atherosclerosis. Adipocytes can also function as phagocytes to uptake and degrade oxidized low-density lipoprotein (Ox-LDL), suggesting that adipocytes possibly involve in clearance of Ox-LDL in blood. The dysfunctional adipocytes might be implicated in the atherogenesis. Some cardioprotective drugs mediate their cardiovascular benefits partly through their direct beneficial effects on adipocytes. Therefore, we hypothesized that adipocytes might be potential target for the treatment of atherosclerosis.

Adipocytes↗

PubMed2004

Proteomics reveals that proteins expressed during the early stage of Bacillus anthracis infection are potential targets for the development of vaccines and drugs.

In this review, we advance a new concept in developing vaccines and/or drugs to target specific proteins expressed during the early stage of Bacillus anthracis (anthrax) infection and address existing challenges to this concept. Three proteins (immune inhibitor A, GPR-like spore protease, and alanine racemase) initially identified by proteomics in our laboratory were found to have differential expressions during anthrax spore germination and early outgrowth. Other studies of different bacillus strains indicate that these three proteins are involved in either germination or cytotoxicity of spores, suggesting that they may serve as potential targets for the design of anti-anthrax vaccines and drugs.

Alanine Racemase↗

PubMed1988

Compartmentation of glycolysis in trypanosomes: a potential target for new trypanocidal drugs.

In African trypanosomes most enzymes of the glycolytic pathway are found in a microbody-like organelle, called the glycosome. The analysis of their structural and functional properties has shown that these glycosomal enzymes possess some specific features which are absent from the cytosolic proteins of trypanosomes and from the glycolytic enzymes of other organisms, where glycolysis is not compartmentalized within an organelle. The specific properties of the glycosomal enzymes may be responsible for the routing of the proteins from their site of synthesis, the cytosol, into the glycosome, or they may be involved in the proper functioning of the enzymes within the organelle. Whatever the role of the unique features, they are potential targets for compounds that could specifically interfere with glycolysis in trypanosomes. Therefore, a detailed study of the glycolytic enzymes of trypanosomes may lead to the development of therapeutically useful drugs against these harmful parasites.

Animals↗

PubMed1995

Ovarian tumour antigens as potential targets for immune gene therapy.

Major new developments in the understanding of the molecular mechanisms involved in immune recognition of self, and immune mediated rejection of foreign antigens, have resulted in the development of a variety of novel therapeutic strategies for the treatment of cancer. Cornerstones of the advances in this area have been the identification of tumour antigens and demonstration of immune recognition of neoplastic cells, most notably in malignant melanoma. There are now a number of clinical immune gene therapy trials in progress for the treatment of cancer by stimulating immune mediated rejection of malignant cells. Here we examine the evidence for immune recognition of ovarian tumour cells and the presence of putative ovarian tumour antigens as potential targets for immune gene therapy of ovarian carcinoma.

Antigen-Presenting Cells↗

PubMed2006

Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's.

Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by the loss of large numbers of forebrain neurons. There are currently no effective AD treatments available and the cause of the disease is unknown in the majority of cases. Because normal neuronal maintenance and survival depends on stimulation of key signaling pathways by a number of neurotrophic factors it has been postulated that reduced signaling by or expression of these factors may promote neurodegeneration. Growing evidence suggests that the transforming growth factor-beta (TGF-beta) signaling pathway may be one such neurotrophic pathway that meets important protective and survival roles in neurons. Here I explore this evidence and discuss the pathway as a potential target for the treatment of neurodegeneration and AD.

Alzheimer Disease↗

PubMed2005

Signaling processes in tumoral neuroendocrine pituitary cells as potential targets for therapeutic drugs.

Pituitary adenomas are neuroendocrine tumors that produce different endocrine and metabolic alterations, including hyperprolactinemia, acromegaly and Cushing's disease. These different clinical features of pituitary tumors are the result of the overproduction of hormones produced by the different pituitary cell types. Recent advances in the understanding of the signaling pathways that control hormone production in pituitary cells provide a source of potential therapeutic targets. In ACTH-secreting cells, the mechanisms that control hormone biosynthesis have been clarified to a great extent, indicating a number of protein kinases and ligand-activated nuclear receptors as targets for experimental drugs. ACTH production requires the activation of signal transduction through the PKA, the MAPK and the CamK pathways. These pathways activate nuclear receptors, including Nur and PPAR gamma. The inhibition of these kinases and nuclear receptors has been shown to produce therapeutic effects in mouse models of Cushing's syndrome. On the other hand, the signaling pathways that control prolactin and growth hormone production also have potential targets. It has been recently shown that SMAD proteins activated by growth factors of the TGF beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Cytokines that bind to the membrane protein gp130 also stimulate the proliferation of these cells. The inhibition of both of these pathways results in the decrease of tumor growth in animal models of prolactinoma. Therefore, the study of signaling pathways that control hormone production and proliferation is a good source of candidate targets in pituitary tumors.

Adrenocorticotropic Hormone↗

PubMed2006

Focal adhesion kinase: a potential target in cancer therapy.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in signal transduction pathways that are initiated at sites of integrin-mediated cell adhesions and by growth factor receptors. FAK is a key regulator of survival, proliferation, migration and invasion: processes that are all involved in the development and progression of cancer. FAK is also linked to oncogenes at both a biochemical and functional level. Moreover, overexpression and/or increased activity of FAK is common in a wide variety of human cancers, implicating a role for FAK in carcinogenesis. Given the important role of FAK in a large number of processes involved in tumorigenesis, metastasis and survival signalling FAK should be regarded as a potential target in the development of anti-cancer drugs. Therefore, selective inhibitors of FAK need to be developed. Combination of these selective FAK inhibitors with cytotoxic agents could be a very promising anti-cancer therapy.

Animals↗

PubMed2001

Somatically mutated regions of immunoglobulin on human B-cell lymphomas code for peptides that bind to autologous major histocompatibility complex class I, providing a potential target for cytotoxic T cells.

Lymphoma-derived immunoglobulin idiotype (Id) is a well-characterized, tumor-specific antigen on B-cell malignancies. Immunotherapy using lymphoma immunoglobulin can lead to clinical responses mostly associated with anti-Id antibody. We cloned the Id from B-cell lymphomas, sequenced them, and used bioinformatics to select autologous MHC class I binding peptides from somatically mutated regions of the lymphoma Id. Peptides from patients who were HLA-A1, HLA-A2, HLA-A3, or HLA-A11 positive were analyzed in the T2 stabilization assay and a competitive peptide-binding assay. By both methods, approximately half of the peptides analyzed, regardless of HLA type, bound with intermediate or high affinity. Peptide binding affinity was similar to viral peptide sequences known to provide targets for cytotoxic T cells. Further investigation of lymphocyte responses to stimulation by autologous Id peptides versus Id peptides from other patients revealed that three of five patients in complete remission or with low volume, stable disease responded to self-peptides by IFN-gamma secretion greater than that seen with non-self peptides, whereas none of five patients with progressive disease responded to their own lymphoma Id. We have shown that mutated regions of lymphoma Id contain MHC class I binding peptides that are potential targets for cytotoxic T cells. Immunotherapy using the tumor-specific mutated regions from lymphoma Id avoids the need to break innate tolerance toward the germ-line protein sequences present on normal and malignant B cells.

Amino Acid Sequence↗

PubMed2000

The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function.

Signalling by the tumour necrosis factor receptors (TNFR) is thought to be mediated by the binding of the trimeric ligand TNF to three monomeric subunits of the receptor. This ligand induced trimerisation model of TNFR signalling is mainly supported by crystallographic data of the p60 TNFR-1 and TNFbeta complex in which the trimeric ligand interdigitates between the individual receptor chains and prevents the receptor subunits from interacting with each other. Recently, a domain NH(2)-terminal to the ligand binding domain in the extracellular region of p60 TNFR-1, p80 TNFR-2 and Fas was identified that mediates receptor self association before ligand binding. This pre-ligand binding assembly domain or PLAD is critical for assembly of functional receptor complexes on the cell surface and may provide a potential target in the design of future novel therapeutics against diseases mediated by members of the TNFR family of receptors.

Arthritis, Rheumatoid↗

PubMed1992

The insulinomimetic agents H2O2 and vanadate stimulate tyrosine phosphorylation of potential target proteins for the insulin receptor kinase in intact cells.

H2O2 and vanadate are known insulinomimetic agents. Together they induce insulin's bioeffects with a potency which exceeds that seen with insulin, vanadate or H2O2 alone. We have previously shown that a combination of H2O2 and vanadate, when added to intact cells, rapidly stimulates protein tyrosine phosphorylation, owing to the inhibitory effects of these agents on intracellular protein tyrosine phosphatases (PTPases). Employing Western blotting with anti-phosphotyrosine antibodies, we have now identified in Chinese-hamster ovary (CHO) cells transfected with a wild-type insulin-receptor gene (CHO.T cells) several proteins (e.g. pp180, 125, 100, 60 and 52) whose phosphotyrosine content is rapidly increased upon treatment of the cells with a combination of insulin and 3 mM-H2O2. Tyrosine phosphorylation of these and additional proteins was further potentiated when 100 microM-sodium orthovanadate was added together with H2O2. The effects of insulin, insulin/H2O2, and H2O2/vanadate on tyrosine phosphorylation were markedly decreased in CHO cells transfected with an insulin-receptor gene where the twin tyrosines 1162 and 1163 were replaced with phenylalanine (CHO.YF-3 cells). Similarly, most of these proteins failed to undergo enhanced tyrosine phosphorylation in parental CHO cells incubated in the presence of insulin or the insulinomimetic agents. Our findings suggest that inhibition of PTPase activity by H2O2/vanadate augments the autophosphorylation of tyrosines 1162 and 1163 of the insulin receptor kinase, leading to its activation in an insulin-independent manner. As a result, tyrosine phosphorylation of potential targets for this enzyme takes place. Failure of H2O2/vanadate to induce phosphorylation of these proteins in receptor mutants lacking these twin tyrosine residues supports this hypothesis.

Animals↗

PubMed1995

Defining potential targets for immunotherapy in Burkholderia cepacia infection.

Burkholderia cepacia has become a serious source of infection in patients with cystic fibrosis. Antibiotic therapy is difficult as the bacteria are intrinsically resistant to most antibiotics. The present study compared the antibody response by immunoblot of 50 negative control sera, 22 patients with cystic fibrosis and no evidence of B. cepacia, 9 clinically well patients with cystic fibrosis colonised by B. cepacia and 5 patients with cystic fibrosis and deteriorating or fatal B. cepacia infection. Nineteen antigenic bands varying in apparent molecular weights from 19 to 170 kDa were identified. Two bands at 19 and 21 kDa were only present when the organism was grown in an iron-deficient medium. The band at 30 kDa was identified as a porin and the possession of IgG antibody carried a statistically significant (P = 0.00003) better prognosis. This antigen was thus a potential target for immunotherapy.

Antibodies, Bacterial↗

PubMed2003

Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease.

Although cannabinoids have been recreationally employed for thousands of years, it was not until the discovery of their specific receptors, in the early nineties, that the molecular basis of cannabinoid activity have began to be understood. Growing research in this field has demonstrated not only that the action of cannabinoids in mammals is mainly receptor-mediated, but also that endogenous cannabinoids, such as anandamide, are produced, metabolized, and taken up across the cell membrane through a facilitated uptake process. The exogenous administration of cannabinoids, as well as the manipulation of their endogenous levels have been related to a variety of effects, such as analgesia, impairment of cognition and learning, appetite enhancement and peripheral vasodilation. Hence, the endocannabinoid system, including the CB1 and CB2 receptors, the metabolizing enzyme fatty acid amide hydrolase and the anandamide transporter, is a potential target for the development of novel therapeutic drugs in the treatment of various conditions, such as pain, feeding disorders and vascular disease among others. Although most of the research in the field of cannabinoids has been focused on their effects in the central nervous system, a growing line of evidence indicates that cannabinoids can also play a major role in the control of physiopathological functions in the cardiovascular system. In this context, endocannabinoids have been proposed as novel possible hypotensive agents, and have been involved in the hypotension observed in septic shock, acute myocardial infarction and cirrhosis. In addition, a protective role for endocannabinoids has been described in ischemia.

Animals↗

PubMed2004

Biodistribution and targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles in subcutaneous murine tumor model.

PURPOSE: In order to develop a safe and effective systemically-administered biodegradable nanoparticle delivery system for solid tumors, the comparative biodistribution profiles of gelatin and poly(ethylene-glycol)(PEG)-modified (PEGylated) gelatin nanoparticles was examined in subcutaneous Lewis lung carcinoma (LLC)-bearing female C57BL/6J mice. METHODS: Type-B gelatin and PEGylated gelatin nanoparticles were radiolabeled ((125)I) for the in vivo biodistribution studies after intravenous (i.v.) administration through the tail vein in LLC-bearing mice. At various time intervals, the mice were sacrificed and blood, tumor, and major organs harvested for analysis of radioactivity corresponding to the localization of the nanoparticles. Percent recovered dose was determined and normalized to the weight of the fluid or tissue sample. Non-compartmental pharmacokinetic analysis was performed to determine the long-circulating property and preferential tumor targeting potential of PEGylated gelatin nanoparticles in vivo. RESULTS: From the radioactivity in plasma and various organs collected, it was evident that the majority of PEGylated nanoparticles were present either in the blood pool or taken up by the tumor mass and liver. For instance, after 3 h, the concentrations of PEGylated gelatin nanoparticles was almost 2-fold higher in the blood pool than the control gelatin nanoparticles. PEGylated gelatin nanoparticles remained in the blood pool for a longer period of time due to the steric repulsion effect of the PEG chains as compared to the gelatin nanoparticles. In addition, approximately 4-5% of the recovered dose of PEGylated gelatin nanoparticles was present in the tumor mass for up to 12 h. The plasma and the tumor half-lives, the mean residence time, and the area-under-the-curve of the PEGylated gelatin nanoparticles were significantly higher than those for the gelatin nanoparticles. CONCLUSIONS: The results of this study show that PEGylated gelatin nanoparticles do possess long circulating properties and can preferentially distribute in the tumor mass after systemic delivery.

Animals↗

PubMed2005

CCK2 gastrin receptor as a potential target for therapy in leukaemia cell lines.

The gastrin CCK2 pathway has been implicated in the development of various cancers including leukaemia. An autocrine or intracrine pathway may exist in the leukaemia cell that is involved in stimulating proliferation. We tested four leukaemia cell lines, KU812, ML-1, MOLT-4 and U937 for the existence of the CCK2 receptor and gastrin precursor protein using immunoblotting. We also assessed the effect of CCK2 antagonist PD 135 and both gastrin 17 and glycine-extended gastrin on the proliferation of the cell lines. We found immunoreactive CCK2 and gastrin precursors present in all 4 cell lines. We also observed a stimulatory effect on proliferation by gastrin and glycine-extended gastrin on 2 and 3 of the cell lines respectively and an inhibitory effect of PD 135 on all 4 cell lines. These results demonstrate that the gastrin-gastrin receptor axis is a potential target for new therapeutic strategies.

Cell Line, Tumor↗

PubMed2004

The Fas receptor-1,4,5-IP3 cascade: a potential target for treating heart failure and arrhythmias.

Activation of the Fas receptor in various cell types, including myocytes, triggers apoptotic as well as nonapoptotic effects. Recent studies suggest that Fas activation in the heart participates in the development of major pathologies such as myocarditis and ischemic/reperfusion insults, which are manifested by arrhythmias and mechanical dysfunction. To decipher the contribution of the Fas/FasL pathway to myocardial pathologies, we have investigated the functional consequences of Fas activation in normoxic and hypoxic ventricular myocytes. Our major findings were as follows. (1) Although Fas is constitutively expressed in ventricular myocytes, normoxic myocytes are resistant to Fas-mediated apoptosis. In contrast, hypoxia predisposes myocytes to apoptosis induced by Fas activation. The underlying mechanism is a shift in the balance between proapoptotic proteins (including Fas) and antiapoptotic proteins toward the former. (2) In normoxic myocytes, Fas activation causes a wide range of functional disturbances, which include reduction in resting potential and action potential amplitude, prolonged action potential duration, development of delayed and early after-depolarizations, occasionally culminating into arrhythmias, diastolic [Ca(2+)](i) level increase, decreased I(to) and increased I(Ca,L). (3) The above-mentioned effects in normoxic myocytes (but not Fas-mediated apoptosis in hypoxic myocytes) depend on the phospholipase C --> 1,4,5-IP(3) --> SR [Ca(2+)](i) release cascade. (4) Inhibition of tyrosine kinases with genistein blocks both the apoptotic and nonapoptotic consequences of Fas activation in ventricular myocytes. Based on these studies we propose that tyrosine phosphorylation in ventricular myocytes can serve as a novel potential target for attenuating Fas-mediated dysfunction in normoxic and hypoxic myocardium.

Animals↗

PubMed2003

Nociceptin/orphanin FQ and its receptor--potential targets for pain therapy?

The neuropeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). Both N/OFQ and the NOP receptor share a high degree of homology with classical opioid peptides and opioid receptors, respectively, and use similar signal transduction pathways as classical opioids. The NOP receptor has thus been regarded as the fourth member of the opioid receptor family. Despite this close relationship, 7 years of research have demonstrated that the N/OFQ system has a distinct pharmacological profile and serves different physiological functions. In particular, its role in the control of pain and analgesia at different levels of integration appears quite different from that of classical opioids. The recent development of specific antagonists at the NOP receptor and of NOP receptor or N/OFQ precursor knock-out mice have generated new insights into the role of N/OFQ in pain processing and help to evaluate the N/OFQ-NOP system as a potential target for new analgesic drugs.

Animals↗

PubMed2002

Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.

Vascular endothelial growth factor A (VEGF-A), the founding member of the vascular permeability factor (VPF)/VEGF family of proteins, is an important angiogenic cytokine with critical roles in tumor angiogenesis. This article reviews the literature with regard to VEGF-A's multiple functions, the mechanisms by which it induces angiogenesis, and its current and projected roles in clinical oncology. VEGF-A is a multifunctional cytokine that is widely expressed by tumor cells and that acts through receptors (VEGFR-1, VEGFR-2, and neuropilin) that are expressed on vascular endothelium and on some other cells. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis. Recently, VEGF-A has also been shown to induce lymphangiogenesis. Measurements of circulating levels of VEGF-A may have value in estimating prognosis, and VEGF-A and its receptors are potential targets for therapy. Recognized as the single most important angiogenic cytokine, VEGF-A has a central role in tumor biology and will likely have an important role in future approaches designed to evaluate patient prognosis. It may also become an important target for cancer therapy.

Capillary Permeability↗