Somatostatin analogues are among the first peptide based
Somatostatin analogues are among the first peptide-based drugs used in cancer imaging and therapy (for review see Reubi, 2003). Treatment of tumors by the use of peptide analogues labeled with cytotoxic agents acting via specific receptors is also under investigation for neuropeptide Y (Koglin and Beck-Sickinger, 2004) and feasible for any other peptide–receptor systems that are highly expressed in certain types of cancer (for review see Reubi, 2003, Schally and Nagy, 2004, Schally et al., 2004).
The neuropeptide galanin has also been suggested to be involved in the carcinogenesis and pathophysiology of neuroendocrine tumors based on the development of estrogen-induced tumors in estrogen-sensitive rats and decreased galanin gene expression after inhibition of tumor formation (Gregg et al., 1996, Hsu et al., 1990, Hyde and Howard, 1992, Wynick et al., 1993, Wynick et al., 1998).
GAL is a 29–30 amino ionomycin sale peptide with a widespread distribution throughout the central and peripheral nervous system (Kordower et al., 1992, Tatemoto et al., 1983). The actions of galanin are mediated through interaction with at least three specific G protein-coupled receptor subtypes, namely GalR1, GalR2 and GalR3 (Branchek et al., 2000). This review summarizes the current knowledge of galanin and galanin receptor expression in a variety of human cancers.
Expression of galanin peptide in human neoplasias
Expression of galanin receptors
In vivo and in vitro effects of galanin on cell proliferation Additional arguments in favor of a potential role of galanin in cancer treatment are the studies by El-Salhy et al. showing that triple therapy using galanin, octreotide and serotonin cause regression of rat colon carcinoma and human colon cancer xenographs. This treatment induces tumor necrosis and apoptosis in tumor cells (El-Salhy, 2004, El-Salhy and Dennerqvist, 2004, El-Salhy and Sitohy, 2002, El-Salhy et al., 2003, Iishi et al., 1995). Antiproliferative activity and induction of apoptosis was also observed in vitro in a colon carcinoma cell line (El-Salhy and Starefeldt, 2003). Accordingly, in a recent study we showed that in human SH-SY5Y neuroblastoma cells transfected with GalR2, activation of the receptor upon galanin treatment completely inhibited cell proliferation and induced apoptosis (Berger et al., 2004). In contrast, in the pituitary gland galanin exhibits a growth promoting effect in several rodent model systems (Cai et al., 1999, Hsu et al., 1990, Kaplan et al., 1988, O’Halloran et al., 1990, Perumal and Vrontakis, 2003, Wynick et al., 1993). Galanin receptors have been shown to exhibit mitogenic signaling properties for example via the MAP kinase pathway, which plays an important role in cell proliferation (Hammond et al., 1996, Seger and Krebs, 1995, Seufferlein and Rozengurt, 1996, Wittau et al., 2000). Accordingly, galanin supports the clonal growth of certain small cell lung cancer cell lines like it has been demonstrated for a variety of other neuropeptides such as vasopressin, bradykinin, neurotensin, bombesin and gastrin-releasing peptide, which have been proposed to act as autocrine and paracrine growth factors (Cuttitta et al., 1985, Rozengurt, 1995, Sethi et al., 1992, Sethi and Rozengurt, 1991a, Sethi and Rozengurt, 1991b, Sorenson et al., 1981). In human Bowes melanoma cells, we were not able to observe an influence of galanin on their proliferation rate.
Conclusion The application of agonists that have been labeled with radioactive isotopes or cytotoxic agents is dependent on the ability of the peptide to internalize upon receptor–ligand interaction on the cell surface. It has been shown for GalR1 and GalR2 that receptor internalization can occur upon galanin binding (Berger et al., 2004, Wang et al., 1998, Xia et al., 2004). The exact identification of the receptor subtype that is responsible for the observed binding is necessary for specific agonist development and is hindered by the lack of human subtype-specific antibodies and highly specific analogues which could be used for discrimination in receptor autoradiography. RT-PCR analysis reveals that receptors frequently appear to be co-expressed in individual tumors and might reflect an overestimation of the real contribution of a specific receptor due to the high sensitivity of the method.