Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors

Palma, Carla; Nardelli, Federica; Manzini, Stefano; Maggi, Carlo Alberto

doi:10.1038/sj.bjc.6690039

Cited by 59 publications

(46 citation statements)

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“…In in vitro assays, MEN 11467 completely inhibited SPtriggered U373 MG proliferation and cytokine release leaving unaltered the basal or IL-1β-induced responses as a proof of its specificity (Palma et al, 1999a). Moreover, MEN 11467 showed a long-lasting inhibitory activity, probably due to its very slowly reversible binding to the human tachykinin NK 1 receptor (Palma et al, 1999b).…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, these antagonists were more potent in inhibiting late rather than early phases of SP-induced inositol monophosphate accumulation and their antagonisms were enhanced by drug preincubation and barely affected by removal of unbound drug from the external medium, suggesting that they bound in a tight manner to the receptor (Palma et al, 1999b). Interestingly, MEN 11467 was able to completely inhibit the SPinduced proliferation, both in terms of DNA synthesis and increase of cell number, in U373 MG cells without affecting both the basal or IL-1β-stimulated cell growth (Palma et al, 1999a).…”

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confidence: 86%

“…On the contrary they had virtually no affinity (K i values ≥ 10 000 nM) for rat or murine tachykinin NK 1 receptors (Cirillo et al, 1998a(Cirillo et al, , 1998b. Receptor blockade by both antagonists resulted in a powerful and complete inhibition of functional U373 MG responses induced by SP, such as accumulation of the second messenger inositol monophosphate or interleukin-6 release (Palma et al, 1999a(Palma et al, , 1999b. Moreover, these antagonists were more potent in inhibiting late rather than early phases of SP-induced inositol monophosphate accumulation and their antagonisms were enhanced by drug preincubation and barely affected by removal of unbound drug from the external medium, suggesting that they bound in a tight manner to the receptor (Palma et al, 1999b).…”

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confidence: 99%

“…Tachykinins exert their actions through activation of G-protein coupled receptors, labelled NK 1 , NK 2 , NK 3 ; SP is the preferential endogenous ligand for the tachykinin NK 1 receptor (Maggi et al, 1993;Otsuka and Toshioka, 1993). In various astrocytic/glial brain tumour-derived cell lines, the presence of tachykinin NK 1 receptor strictly correlates with the effect of SP and/or NKA in increasing DNA synthesis and cellular proliferation Sharif et al, 1996;Palma et al, 1999a). In addition, SP can control many other glial responses such as taurine release, secretion of various cytokines (e.g.…”

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Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

et al. 2000

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Malignant astrocytomas or glioblastomas represent the most common type of primary brain tumour in adults (Salcman and Kaplan, 1986;Hochberg and Pruitt, 1987). High-grade malignant gliomas are inevitably lethal neoplasms and the median survival of patients treated with standard cytoreductive surgery and postoperative radiotherapy is in the range of 1 year. Likewise chemotherapy is of limited effectiveness in the treatment of these tumours and other therapeutic approaches must be explored. Glioblastomas are sensitive to several hormones and growth factors. The presence of receptors for epidermal growth factor, platelet-derived growth factor, insulin-like growth factor-I/II as well as for glucocorticoid, androstenedione and progesterone in malignant gliomas, has been described (Shapiro et al, 1995). Recently, neurotransmitters/neuropeptides have also been found to regulate astrocytoma growth (Sharif, 1998).Substance P (SP), an undecapeptide of the tachykinin family of neuropeptides, is released both in the central and peripheral nervous systems, playing a well established role in neuronal transmission, vasodilatation and motor responses (Maggi et al, 1993). Tachykinins exert their actions through activation of G-protein coupled receptors, labelled NK 1 , NK 2 , NK 3 ; SP is the preferential endogenous ligand for the tachykinin NK 1 receptor (Maggi et al, 1993;Otsuka and Toshioka, 1993). In various astrocytic/glial brain tumour-derived cell lines, the presence of tachykinin NK 1 receptor strictly correlates with the effect of SP and/or NKA in increasing DNA synthesis and cellular proliferation Sharif et al, 1996;Palma et al, 1999a). In addition, SP can control many other glial responses such as taurine release, secretion of various cytokines (e.g. interleukin (IL)-6, IL-8, transforming growth factor-β, leukaemia inhibitory factor, granulocyte-macrophage colony stimulating factor) which are thought to be relevant for glioma progression (Gitter et al, 1994;Palma et al, 1995;Palma and Manzini, 1998). In a large number of these studies, the human astrocytoma grade III U373 MG cell line, which expresses a high level of functional tachykinin NK 1 receptor (Lee et al, 1992;Palma et al, 1999b) but not tachykinin NK 2 or NK 3 receptors (Heuillet et al, 1993), were used.The role of SP in glioma activities may be ascribed to a pathological use of normal signal transduction pathways occurring in reactive astrocytes. In fact, SP activates phospholipase C and stimulates the release of IL-6 and prostaglandin E 2 from human fetal astrocytes in culture (Palma et al, 1997), and there is evidence for an up-regulation of this receptor by reactive proliferating astrocytes after transection of the optic nerve (Mantyh et al, 1989). Moreover, SP-immunoreactive astrocytes have been observed in multiple sclerosis plaques (Kostyk et al, 1989) and in the forebrains of human infants (Michel et al, 1986). Interestingly, the involvement of tachykinin NK 1 receptor and SP in glioma progression was not only supported by the functional in vitro stud...

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confidence: 91%

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Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

et al. 2000

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“…5 It has also been shown that activation of NK-1 receptors by SP induces mitogenesis in several melanoma cell lines 6,7 and others tumor cell lines. [8][9][10][11][12][13][14][15][16] SP is also a main mediator in the growth of capillary vessels in vivo and in the proliferation of cultured endothelial cells in vitro, and it has also been shown that NK-1 receptor agonists induced neoangiogenesis. 17 Moreover, the active migration of tumor cells, a crucial requirement for invasion and metastasis, is regulated by SP signals.…”

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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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Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

Perruccio

2013

Methods and Principles in Medicinal Chemistry

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Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors

Cited by 59 publications

References 32 publications

Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft

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

Case Study 2: Bioisosteric Replacements for the Neurokinin 1 Receptor (NK1R)

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