Neurokinin-1 Receptor Antagonists CP-96,345 and L-733,060 Protect Mice from Cytokine-Mediated Liver Injury

Bang, Renate; Sass, Gabriele; Kiemer, Alexandra K.; Vollmar, Angelika M.; Neuhuber, Winfried; Tiegs, Gisa

doi:10.1124/jpet.102.043539

Cited by 72 publications

(83 citation statements)

References 42 publications

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“…This damage may eventually compromise the tachykininergic mechanisms that switch neurogenic responses from their physiological reflexes to a detrimental inflammatory role that perpetuates and intensifies lung injury (5,6,34,43). As mentioned earlier, SP, as a potent proinflammatory mediator, has numerous pathways in signaling transduction within a complex network involving chemokines (12,28,29,39,40,51), cytokines (1,2,11), reactive oxygen/nitrogen species (33,37,39), and other mediators (17,37,51). SP at large in airways may abnormally signal immunoinflammatory cells to generate these mediators through "silent NK receptors" that may not be involved in the cellular responses to SP under the normal physiological condition.…”

Section: Discussionmentioning

confidence: 99%

Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

Wong¹,

Sun²,

Lantz³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.

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Section: Discussionmentioning

confidence: 99%

Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

Wong¹,

Sun²,

Lantz³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Thus, the IC 50 for HEK 293 fibroblast cells was approximately three times higher than the IC 50 for tumor cells, 30 as occurring in the melanoma cell lines studied here. Indeed, in the host, aprepitant exerts beneficial effects in a dose-dependent manner, such as antiemetic, 29 antidepressant, 27 anxiolytic, 28 anti-inflammatory, 42 analgesic, 43 hepatoprotector 42 and neuroprotector. 44 In summary, we describe for the first time the presence of several isoforms of the NK-1 receptor in MEL HO, COLO 858 and COLO 679 human malignant melanoma cell lines.…”

Section: Nk-1 Receptor and Aprepitant In Melanomas M Muñ Oz Et Almentioning

confidence: 99%

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

Muñoz

Rosso

Robles‐Frías

et al. 2010

Laboratory Investigation

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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 mM 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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“…SP, an undecapeptide of the tachykinin peptide family, regulates multiple biological functions by binding to the NK-1 receptor (NK-1R), including cardiovascular and respiratory mechanisms, sensory perception, and response to stress, among others (7)(8)(9)(10). However, one of its most important functions is related to its action as a potent mitogen on some precancerous epithelial lesions and some human cancer cell lines, e.g., glioma, retinoblastoma, neuroblastoma, melanoma, and laryngeal carcinoma as previously reported by our group (6,(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Substance P and NK-1R expression in oral precancerous epithelium

González‐Moles

Brener²,

Ruiz‐Ávila³

et al. 2009

Oncol Rep

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Abstract. The objectives of this study were to investigate the presence and distribution of substance P and neurokinin 1 receptor in oral premalignant epithelium and their relation with the presence of dysplasia, and to analyze whether the expression of substance P can be considered an early oncogenic event in oral carcinogenesis. Substance P and neurokinin 1 receptor expression was immunohistochemically studied in 83 oral carcinomas and adjacent nontumor epithelia. The presence and degree of epithelial dysplasia was assessed according to WHO criteria. The nuclear, cytoplasmic, and membrane expression of substance P and the cytoplasmic and membrane expression of neurokinin 1 receptor were assessed in tumor and adjacent non-tumor epithelium. Nuclear and cytoplasmic expression of substance P in non-tumor epithelium was significantly associated with the presence of epithelial dysplasia (p<0.001) and carcinoma in situ (p=0.021). Nuclear, cytoplasmic, and membrane expressions of substance P in non-tumor epithelium were significantly (p<0.001) associated with its expression in the corresponding tumor. These findings suggest that substance P plays a role in early oral carcinogenesis by promoting the proliferation and growth of premalignant fields. IntroductionThe development of oral carcinoma is a multistep process involving multiple oncogenic alterations (1). Some of these are considered early oncogenic events, including changes in chromosomal regions 3p, 9p, and 17p (2,3). Although tumor suppressor genes and putative oncogenes in these regions have yet to be identified (4), these chromosomal areas are known to be carriers of important cell-cycle and apoptosis-regulating genes. Thus, CDKN2A locus, which encodes for p16 protein, is located in chromosome 9p21, and p53 gene is in chromosome 17p13 (5). These early oncogenic events have been demonstrated in precancerous fields (4) and endow cells with an increased proliferation rate that affords them a growth advantage over epithelial cells of the adjacent healthy oral mucosa. This phenomenon considerably increases the number of target cells in which new oncogenic events can take place, which would ultimately lead to the development of one or more invasive carcinomas (4).There has been increasing interest over the past few years in the role of substance P (SP) in the development and progression of certain types of tumor (6). SP, an undecapeptide of the tachykinin peptide family, regulates multiple biological functions by binding to the NK-1 receptor (NK-1R), including cardiovascular and respiratory mechanisms, sensory perception, and response to stress, among others (7-10). However, one of its most important functions is related to its action as a potent mitogen on some precancerous epithelial lesions and some human cancer cell lines, e.g., glioma, retinoblastoma, neuroblastoma, melanoma, and laryngeal carcinoma as previously reported by our group (6,(11)(12)(13)(14)(15)(16)(17). These observations suggest that SP may play a role in cancer development by acting as a promot...

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Neurokinin-1 Receptor Antagonists CP-96,345 and L-733,060 Protect Mice from Cytokine-Mediated Liver Injury

Cited by 72 publications

References 42 publications

Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

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

Substance P and NK-1R expression in oral precancerous epithelium

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