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

Abstract

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...

Epigenomic Profiling Reveals Novel and Frequent Targets of Aberrant DNA Methylation-Mediated Silencing in Malignant Glioma

“…Although growth suppressive effects have been established for CST6 in breast cancer (29), the effects of TSPYL5, CST6, TACSTD2, and CLIC3 expression on glioma cell growth has not been investigated. It was suggested that one of the TAC1-encoded peptides, substance P, enhances proliferation in a glioma xenograft model (30), and BIK induces apoptosis in glioma cells when reexpressed using a viral vector (31). To ascertain whether these six genes have growth suppressive properties in glioma cell lines in which the endogenous gene is methylated, we first cloned their full-length cDNAs into the pcDNA3.1 mammalian expression vector (also encoding neomycin resistance).…”

“…The exact role of TAC1 in primary human gliomas will, therefore, require additional study; however, the net effect of its reduced expression may depend on the local environment of the tumor. Release of certain cytokines may be immunologically unfavorable for the tumor (e.g., TGF-h), and it is unlikely that these effects would be observed in mouse xenografts (30).…”

Neurokinin-1 Receptor Expression and Its Potential Effects on Tumor Growth in Human Pancreatic Cancer

“…It enhances the secretion of IL-6 and transforming growth factor ␤1 and stimulates DNA synthesis and cell proliferation (Lieb et al, 1998;Palma et al, 1999b). On the other hand, inhibitory effects of SP have been reported in prostate cancer cells (Nagakawa et al, 1998), in murine Colon 26-L5 tumor cells (Ogasawara et al, 1997), in small cell lung cancer cells (Nyeki et al, 1998), and in human glioma U373 MG xenografts transplanted into nude mice (Palma et al, 2000). The reasons why SP exhibits stimulatory effects in one tumor type and inhibitory effects in another are not readily evident and do not seem to be solely dependent on the NK-1R receptor status.…”

“…NK-1R is abundantly present in the rat pituitary and in AtT20 mouse pituitary tumor cells, giving a hint that this receptor might be involved in the pathogenesis of these tumors (Winkler et al, 1995). Furthermore, in human glioma cells, NK-1R stimulated by SP triggers a number of biologic responses that are potentially relevant for tumor growth and progression (Lieb et al, 1997(Lieb et al, , 1998Palma et al, 1999b).…”

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

“…The peptide substance P (SP; also known as TAC1) is a widely distributed neuronal transmitter that, after binding specifically to NK1R, triggers a broad variety of functions (5). It is known that SP can induce tumor cell proliferation, angiogenesis and migration via NK1R, and that the SP/NK1R complex is an integral part of the cancer cell itself, as well as its tumor microenvironment (6).…”