Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that neutral endopeptidase (NEP; EC 3.4.24.11) regulates neuropeptide-induced responses. Recently, Pierart et al. reported that NEP degraded purified interleukin-1 (IL-1) using thymocyte proliferation assay. Since IL-1 is an important cytokine in the immune response and inflammation, we have assessed whether NEP hydrolyzes recombinant human IL-1 beta using three assay systems (bioassay, immunoassay, and HPLC analysis). NEP on the NALM-6 cells (both intact cells and the solubilized plasma membrane fraction) efficiently hydrolyzed Met5-enkephalin and substance P. However, NEP did not significantly decrease the amount of rhIL-1 beta assessed by the growth inhibitory activity of a human melanoma, by the immunoassay, or by the direct analysis on HPLC. Therefore, we conclude that NEP does not significantly hydrolyze rhIL-1 beta. Our results suggest that, in contrast to the regulatory role of NEP in neuropeptide-induced responses, NEP is not a regulatory enzyme for IL-1-induced responses.
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PMID:Neutral endopeptidase (EC 3.4.24.11) does not hydrolyze recombinant human interleukin-1 beta. 171 45

Although some cultured human melanoma cell lines are responsive to melanotropins (melanocyte-stimulating hormones [MSH]), the prevalence and tissue distribution of MSH receptors in melanoma are unknown. We report here the use of an in situ binding technique to demonstrate specific MSH receptors in surgical specimens of human melanoma. The distribution and binding properties of specific MSH binding sites were determined by autoradiography and image analysis after incubation of frozen tumor tissue sections with a biologically active, radiolabeled analogue of alpha-MSH, [125I]iodo-Nle4, D-Phe7-alpha-MSH ([125I]NDP-MSH). In melanoma specimens from 11 patients, 3 showed high levels of specific binding, 5 showed low levels, and in 3 patients specific binding of [125I]NDP-MSH was not detectable. Specific MSH binding sites were present in melanoma cells, but not in adjacent connective or inflammatory tissues. Melanotropins, including alpha-MSH, NDP-MSH, and ACTH, inhibited [125I]NDP-MSH binding in a concentration-dependent manner, whereas unrelated peptides (somatostatin and substance P) did not. The apparent affinity of alpha-MSH for this binding site was in the nanomolar range (EC50 = 2 X 10(-9) M for inhibition of [125I]NDP-MSH binding in situ), similar to that recently described for the murine melanoma receptor. In one patient, analysis of multiple intratumor samples and tumors excised on three separate occasions revealed high levels of specific MSH binding in all samples. These results suggest that endogenous melanotropins may modulate the activities of human melanoma cells in vivo.
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PMID:Melanotropin receptors demonstrated in situ in human melanoma. 234 15

Recent evidence has suggested that stress may suppress the immune system and increase the frequency and severity of viral and neoplastic disease. The mechanisms for stress-induced modulation of immune function are unclear, but several neuropeptides are thought to be involved. Because macrophages play an important role in the host defense against infection and neoplasia, several stress-related neuropeptides were screened in efforts to determine whether these substances affect macrophage-mediated tumoricidal activity. Adrenocorticotropin and noradrenaline each completely blocked the capacity of mouse recombinant interferon-gamma (INF-gamma) to activate murine peritoneal macrophages to a tumoricidal state as measured by the lysis of 125I-UdR-labeled melanoma target cells. Vasoactive intestinal peptide significantly potentiated the suppressive effects of noradrenaline. In contrast, neurotensin markedly enhanced the cytolytic capability of peritoneal macrophages activated with INF-gamma. Several other neuropeptides, including substance P, alpha-endorphin, beta-endorphin, Leu-enkephalin, and Met-enkephalin, had no effect on macrophage activation. These findings demonstrate that selected stress-related neuropeptides and neurohormones significantly modulate the capacity of macrophages to attain a tumoricidal state and suggest that alteration of macrophage function by neuropeptides may be a prominent feature of stress-induced enhancement of neoplastic disease.
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PMID:Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones. 258 37

B16 F1C29 melanoma cells, which are thought to contain and release catecholamines, were implanted in mouse and rat spinal subarachnoid space. B16 F1C29 cell implants augmented the antinociceptive effect of morphine in tail-flick test, and this interaction was blocked by either the alpha 2-adrenergic antagonist idazoxan or the opioid antagonist naloxone. B16 F1C29 cell implants also augmented the antinociceptive effect of the catecholamine re-uptake blocker desipramine. Substance P-induced biting and scratching behaviors were inhibited in mice receiving B16 F1C29 cell implants, and this effect of B16 F1C29 cell implants was blocked by the alpha 2-adrenergic antagonist idazoxan. Mice receiving B16 F1C29 cell implants showed tolerance to intrathecal administration of the alpha 2-adrenergic agonist UK 14304. These results suggest that B16 cell implant-induced antinociception was mediated by catecholamines secreted from the cell implants and acting at spinal alpha 2-adrenergic receptors. Spinal implantation of catecholamine-releasing cells may provide an alternative approach for the therapy of chronic intractable pain and a useful model to study alpha 2-adrenergic receptor tolerance.
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PMID:Antinociception following implantation of mouse B16 melanoma cells in mouse and rat spinal cord. 751 33

An analogue of human melanin-concentrating hormone (MCH) suitable for radioiodination was designed in which Tyr13 and Val19 of the natural peptide were replaced by phenylalanyl and tyrosyl residues: [Phe13, Tyr19]-MCH. The peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and polyhipe PA 500 and PEG-PS resins. The linear MCH peptides with either acetamidomethyl-protected or free cysteinyl residues were purified to homogeneity and cyclized by iodine oxidation, yielding the final product with the correct molecular weight of 2434.61. Radioiodination of the C-terminal tyrosine was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and by high-pressure liquid chromatography. The resulting [125I]-[Phe13, Tyr19]-MCH tracer was the first radiolabelled MCH peptide suitable for radioreceptor assay: saturation binding analysis using mouse G4F-7 melanoma cells demonstrated the presence of 1090 MCH receptors per cell. The dissociation constant (KD) was 1.18 x 10(-10) M, indicating high-affinity MCH receptors on these cells. MCH receptors were also found in other cell lines such as mouse B16-F1 and G4F and human RE melanoma cells as well as in PC12 and COS-7 cells. Competition binding analyses with a number of other peptides such as alpha-MSH, neuropeptide Y, substance P and pituitary adenylate cyclase activating peptide, demonstrated that the binding to the MCH receptor is specific. Atrial natriuretic factor was found to be a weak competitor of MCH, indicating topological similarities between MCH and ANF when interacting with MCH receptors.
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PMID:Synthesis and iodination of human (phenylalanine 13, tyrosine 19) melanin-concentrating hormone for radioreceptor assay. 922 84

Substance P (SP) is a neuropeptide found in both the central and peripheral nervous system. In the skin, SP-containing neurons stimulate the release of histamine from connective tissue mast cells (MC). SP also can potentiate neoangiogenesis and induce dermal fibrosis. MC-derived histamine has potent vasoactive effects, is angiogenic, and promotes tissue fibroplasia. In addition to histamine, MC contain many other angiogenic factors and a variety of cytokines, growth factors, and proteolytic enzymes implicated in tissue remodeling, and normal as well as tumor-associated neoangiogenesis. Many MC-derived factors, including histamine, can enhance melanoma cell growth directly. MC often concentrate around cutaneous melanomas which also frequently are associated with angiogenesis and peritumoral fibrosis. The precise mediators of these responses have not been well defined. We evaluated by immunohistochemistry cutaneous lesions representing stages of progression of malignant melanoma and its precursor lesions for the expression of SP. SP was expressed in 17/25 (68%) primary invasive malignant melanomas, 2/5 (40%) metastatic melanomas, 6/10 (60%) melanomas in situ, 7/12 (58%) atypical (dysplastic) nevi, and 4/10 (40%) spindle and epithelioid cell (Spitz) nevi, but was not detected in any (0/11, 0%) acquired benign melanocytic nevi (p<0.05). Invasive melanomas were immunolabeled in both the intraepidermal and the dermal components of the lesions. For those atypical and Spitz nevi which expressed SP, most of the immunoreactive melanocytes were located at the dermal-epidermal junction overlying areas of papillary dermal fibrosis. The results show differential expression of SP among cutaneous melanocytic lesions and suggest that the expression of this neuropeptide together with other factors may contribute to some of the host responses associated with these lesions.
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PMID:The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions. 950 37

Melanoma represents 1% of all cancers and accounts for approximately 65% of skin cancer deaths. At present, effective treatment does not exist. Substance P (SP) is a neuropeptide expressed in invasive malignant melanomas. We studied the in vitro growth inhibitory capacity of the potent and long-acting neurokinin-1 (NK1) receptor antagonist L-733 060 at concentration ranges of 2.5-20 microM, 10-30 microM and 20-50 microM in the melanoma cell lines COLO 858, MEL H0 and COLO 679, respectively. A Coulter counter was used to determine the number of viable cells, and the tetrazolium compound 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulphophenyl)-2H-tetrazolium, inner salt (MTS) colorimetric method was used to evaluate cell proliferation. L-733 060 inhibited the growth of all three cell lines in a dose-dependent manner. The 50% inhibition concentration (IC(50)) was 8.7 microM at 48 h and 7.1 microM at 96 h for COLO 858, 27.5 microM at 24 h and 18.9 microM at 48 h for MEL H0, and 33.8 microM at 30 h and 31.5 microM at 72 h for COLO 679. These findings indicate that the NK1 receptor antagonist L-733 060 acts as an antitumoral agent. This action, shown here for the first time, suggests that the NK1 receptor antagonist L-733 060 could be a promising therapeutic drug in the treatment of the human melanoma.
Melanoma Res 2004 Jun
PMID:Antitumoral action of the neurokinin-1 receptor antagonist L-733 060 on human melanoma cell lines. 1517 86

The possibility of links between psychosocial factors and cancer incidence and progression has generated considerable scientific and public interest. Tachykinins, including substance P, neurokinin A and B, hemokinin-1 and endokinins, are a family of neuropeptides, acting through three types of transmembrane G-protein coupled receptors denoted NK1, NK2 and NK3. Besides their role as neurotransmitters in peripheral and central nervous system, tachykinins and their receptors are also expressed in several non neuronal cells contributing to the fine connections between nervous systems and peripheral organ system such as respiratory, cardiovascular, immune, endocrine, gastrointestinal and genitourinary. Being so much involved in regulating physiological functions, they, of course, can concur to pathological conditions including cancer. Tachykinins can act on different steps of carcinogenesis. Tumors expressing NK receptors, such as astrocytoma, glioma, neuroblastoma, pancreatic cancer and melanoma, can misuse tachykinin-induced signaling, operating in normal cells, to promote proliferation and survival of cancer cells and to release cytokines and soluble mediators favoring tumor growth. In neuroblastoma, breast and prostate carcinomas tachykinins facilitate tumor metastatic infiltration in the bone marrow. In neuroendocrine carcinoma, tachykinins are responsible of symptoms associated with these pathologies including flushing, diarrhea, wheezing and right heart disease. In addition, regardless tumor histology, tachykinins may favor cancer incidence and metastatic progression by influencing blood flux and neovascularization in tumor formation as well as inducing immunosuppression mediated by neurogenic inflammation due to stress or surgery. However, the precise involvement of tachykinins in cancer pathologies and the potentiality to become effective pharmacological drug targets remain to be fully defined.
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PMID:Tachykinins and their receptors in human malignancies. 1691 32

Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 microM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.
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PMID:The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. 2045 80

Substance P, a member of the tachykinin family, is expressed in primary invasive malignant melanomas, metastatic melanomas, melanomas in situ, atypical naevi, and spindle and epithelioid cell naevi. The role of substance P in cancer development and progression is not clear. Radiotherapy, which is used extensively in the treatment of malignancies, alters substance P levels. It is, however, not known whether radiotherapy affects substance P levels in melanomas or in the tumor microenvironment. Given the fact that melanomas express substance P, possible radiation-induced changes in substance P content may underlie their radio-resistance. Hence, the aim of the present study was to determine the effects of radiotherapy on the growth of B16F10 melanomas as well as on the tumor and systemic expression of substance P. In vivo exposure of tumor-bearing C5BL/6 mice to ionizing radiation (45 Gy administered in three fractions) arrested tumor growth for three weeks and induced 3-fold increases in survival, as well as decreasing substance P levels in primary tumors and the surrounding skin. Although radiotherapy was applied locally (1 x 1 cm) at the mid-flank region of the animal, it also induced systemic changes in the levels of substance P. Specifically, radiotherapy decreased substance P levels in skin distant from the radiation field as well as in the lungs and adrenals. In order to understand the significance of this effect, B16F10 cells and cells made from metastatic lesions (B16LNAD cells) were treated with substance P. Substance P inhibited the growth of B16F10 and B16LNAD cells and further potentiated the inhibitory effects of radiotherapy. These findings demonstrate for the first time that substance P inhibits melanoma growth, and that radiotherapy-induced decreases in substance P levels may underlie the radio-resistance of melanomas.
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PMID:Radiotherapy-induced decreases in substance P levels may potentiate melanoma growth. 2147 32


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