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

In the presence of descending modulatory inputs, the stomatogastric ganglion (STG) of the lobster Homarus americanus generates a triphasic motor pattern, the pyloric rhythm. Red pigment-concentrating hormone (RPCH) and Cancer borealis tachykinin-related peptide (CabTRP) are colocalized in a pair of fibers that project into the neuropil of the STG. When the STG was isolated from anterior ganglia modulatory inputs, the lateral pyloric (LP) and pyloric (PY) neurons became silent, whereas the anterior burster (AB) and pyloric dilator (PD) neurons were rhythmically active at a low frequency. Exogenous application of 10(-6) m RPCH activated the LP neuron but not the PY neurons; 10(-6) m CabTRP activated the PY neurons but not the LP neuron. The actions of RPCH on the LP neuron and CabTRP on the PY neurons persisted when the rhythmic drive from the PD and AB neurons was removed, suggesting that the LP and PY neurons are direct targets for RPCH and CabTRP respectively. Coapplication of 10(-6) m RPCH and 10(-6) m CabTRP elicited triphasic motor patterns with phase relationships resembling those in a preparation with modulatory inputs intact. In summary, cotransmitters acting on different network targets act cooperatively to activate a complete central pattern-generating circuit.
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PMID:Colocalized neuropeptides activate a central pattern generator by acting on different circuit targets. 1188 May 17

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(alphaq) and G(alpha12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(alphaq) and stimulating G(alpha12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the G(alphaq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(alpha12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a "biased agonist" mechanism. 1193 11

Small cell lung cancers (SCLCs), many non-SCLCs, and other cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel bradykinin antagonist dimer, CU201 (B9870), that acts as a "biased agonist" for neuropeptides by blocking G(alphaq) signaling and activating G(alpha12,13) signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c(max) was 5773 ng/ml (5 microM), and the decay was biexponential. When fitted to a two-compartment model, the t(1/2alpha) was 14.4 min, and the t(1/2beta) was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.
Clin Cancer Res 2002 May
PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines in vitro and in vivo and produces synergistic growth inhibition in combination with other antitumor agents. 1200 49

We are examining how extracellular peptidase activity sculpts the peptidergic actions of modulatory projection neurons on rhythmically active neuronal circuits, using the pyloric circuit in the stomatogastric ganglion (STG) of the crab Cancer borealis. Neurally released peptides can diffuse long distances to bind to their receptors. Hence, different neurons releasing the same neuropeptide into the same neuropil may reach the same receptor complement. However, extracellular peptidases can limit neuropeptide diffusion and terminate its actions. Distinct versions of the pyloric rhythm are elicited by selective activation of different projection neurons, including those with overlapping sets of cotransmitters. Two of these projection neurons, modulatory commissural neuron 1 (MCN1) and the modulatory proctolin neuron (MPN), contain the neuropeptide proctolin plus GABA. MCN1 also contains Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia is not fully responsible for the distinct actions of MCN1 and MPN. Because there is aminopeptidase activity in the STG that terminates proctolin actions, we tested the hypothesis that the differences in the actions of MCN1 and MPN that are not mediated by CabTRP Ia result from the differential actions of aminopeptidase activity on proctolin released from these two projection neurons. We found that the pyloric circuit response to these two projection neurons becomes more similar when this aminopeptidase activity is blocked. This result supports the hypothesis that extracellular peptidase activity enables different projection neurons to use the same neuropeptide transmitter for eliciting distinct outputs from the same neuronal circuit.
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PMID:Extracellular peptidase activity tunes motor pattern modulation. 1201 36

The pericardial organs (POs) are a pair of neurosecretory organs that surround the crustacean heart and release neuromodulators into the hemolymph. In adult crustaceans, the POs are known to contain a wide array of peptide and amine modulators. However, little is known about the modulatory content of POs early in development. We characterize the morphology and modulatory content of pericardial organs in the embryonic lobster, Homarus americanus. The POs are well developed by midway through embryonic (E50) life and contain a wide array of neuromodulatory substances. Immunoreactivities to orcokinin, extended FLRFamide peptides, tyrosine hydroxylase, proctolin, allatostatin, serotonin, Cancer borealis tachykinin-related peptide, cholecystokinin, and crustacean cardioactive peptide are present in the POs by approximately midway through embryonic life. There are two classes of projection patterns to the POs. Immunoreactivities to orcokinin, extended FLRFamide peptides, and tyrosine hydroxylase project solely from the subesophageal ganglion (SEG), whereas the remaining modulators project from the SEG as well as from the thoracic ganglia. Double-labeling experiments with a subset of modulators did not reveal any colocalized peptides in the POs. These results suggest that the POs could be a major source of neuromodulators early in development.
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PMID:Neuromodulatory complement of the pericardial organs in the embryonic lobster, Homarus americanus. 1220 43

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting
Eur J Cancer 2003 May
PMID:Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. 1273 6

The neurokinin-1 receptor (NK-1R) and its ligand substance P (SP) are involved in the pathogenesis of certain neural tumors. Because nerves are significantly altered in pancreatic cancer, evidence for alteration of this pathway in human pancreatic cancer was sought. Expression of NK-1R was analyzed by real-time quantitative RT-PCR, in situ hybridization, immunohistochemistry, and Western blot analysis in normal human pancreatic and pancreatic cancer tissue samples and in pancreatic cancer cell lines. Furthermore, the influence of SP analogs and of the NK-1R antagonist MEN 11467 on pancreatic cancer cell growth was analyzed by sulforhodamine B (SRB) assay. By real-time quantitative RT-PCR, NK-1R mRNA was increased 36.7-fold (p < 0.001) in human pancreatic cancer samples compared with normal controls. Enhanced NK-1R expression levels were not related to tumor grade but were associated with advanced tumor stage and poorer prognosis. By in situ hybridization and immunohistochemistry, NK-1R mRNA and immunoreactivity were only occasionally weakly present in acinar and ductal cells in the normal pancreas. In contrast, moderate to strong NK-1R mRNA signals and immunoreactivity were present in most cancer cells. By Western blot analysis, NK-1R was increased 26-fold (p < 0.01) in pancreatic cancer samples in comparison to normal controls. NK-1R mRNA was detected in five pancreatic cancer cell lines by real-time quantitative RT-PCR, with the highest levels in CAPAN-1 cells and the lowest in ASPC-1 cells. SP analogs stimulated pancreatic cancer cell growth, depending on the NK-1R expression level, and this effect could be blocked by a selective NK-1R antagonist. These findings illustrate that the NK-1R pathway is activated in human pancreatic cancer and has the potential to contribute to cancer cell growth, thus suggesting the existence of a neuro-cancer cell interaction in vivo.
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PMID:Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. 1274 82

[Arg(6),D-Trp(7,9),N(me)Phe(8)]-substance P (6-11) (SP-G) is a novel anticancer agent that has recently completed phase I clinical trials. SP-G inhibits mitogenic neuropeptide signal transduction and small cell lung cancer (SCLC) cell growth in vitro and in vivo. Using the SCLC cell line series GLC14, 16 and 19, derived from a single patient during the clinical course of their disease and the development of chemoresistance, it is shown that there was an increase in responsiveness to neuropeptides. This was paralleled by an increased sensitivity to SP-G. In a selected panel of tumour cell lines (SCLC, non-SCLC, ovarian, colorectal and pancreatic), the expression of the mitogenic neuropeptide receptors for vasopressin, gastrin-releasing peptide (GRP), bradykinin and gastrin was examined, and their sensitivity to SP-G tested in vitro and in vivo. The tumour cell lines displayed a range of sensitivity to SP-G (IC(50) values from 10.5 to 119 microM). The expression of the GRP receptor measured by reverse transcriptase-polymerase chain reaction, correlated significantly with growth inhibition by SP-G. Moreover, introduction of the GRP receptor into rat-1A fibroblasts markedly increased their sensitivity to SP-G. The measurement of receptor expression from biopsy samples by polymerase chain reaction could provide a suitable diagnostic test to predict efficacy to SP-G clinically. This strategy would be of potential benefit in neuropeptide receptor-expressing tumours in addition to SCLC, and in tumours that are relatively resistant to conventional chemotherapy.
Br J Cancer 2003 Jun 02
PMID:Increased gastrin-releasing peptide (GRP) receptor expression in tumour cells confers sensitivity to [Arg6,D-Trp7,9,NmePhe8]-substance P (6-11)-induced growth inhibition. 1277 99

Both first-hand and second-hand [i.e. side-stream cigarette smoke (SSCS)] exposure to cigarette smoke is known to damage the lungs, alter the immune system, and predispose individuals to the development of emphysema and lung cancer. Previous work from these laboratories has demonstrated that administration of aerosolized substance P (SP) was capable of protecting the pulmonary and immune systems from damage due to environmental toxicants (e.g. hydrocarbon exposures). In the present study, the effects of SP on SSCS exposure were examined. Treatment of mice exposed to SSCS with aerosolized SP prevented pathological cellular and functional changes in the lung as reflected by prevention of damage to airway basement membranes/endothelial cells and preservation of normal airway dynamic compliance. Further, SP treatment reduced and/or prevented the occurrence of micronuclei formation in cells isolated from mice exposed in vivo to SSCS (an indicator of DNA/genetic damage). Finally, in an experimental in vivo lung cancer model, SP therapy significantly reduced the numbers of lung tumors, increased animal survival, and activated pulmonary immune defense mechanisms. Thus, aerosolized SP therapy appears to be capable of inhibiting preventing and/or reversing the cellular and genetic precursors of emphysema and malignancy that often result from exposure to cigarette smoke.
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PMID:Aerosolized substance P protects against cigarette-induced lung damage and tumor development. 1288 98

Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.
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PMID:Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. 1288 99


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