Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation

Abstract

(SSR and DR, respectively), we characterized the expression of SSR and DR subtypes in the non-small-cell lung cancer line Calu-6, and then we evaluated the effect on cell proliferation of SS/D chimeric molecules (BIM-23A387 and BIM-23A370), which bind with high affinity both sst2 and D2R, and compared the results with those obtained by using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Because Calu-6 cells produce insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) peptides, which play a role in the autocrine/paracrine control of cell growth, we also investigated the effects of chimeric compounds on secretion and expression of IGF system components. Relative high levels of sst2 and the long isoform of the D2R were detected by real-time RT-PCR and Western blot in Calu-6, together with sst5 and to a lesser extent sst3 and D4R. BIM-23A387 and BIM-23A370 significantly inhibited growth of Calu-6, whereas IGF-IGFBP secretion or expression was unaffected, suggesting a direct inhibitory effect. The inhibition of cell growth, measured by both [ 3 H]thymidine incorporation and cell count, was significantly lower when individual SSA and DA control peptides or subtype-specific SSA and DA were tested. BIM-23A370 was more potent than BIM-23A387 (P Ͻ 0.001). These findings show that SS/D chimeras can inhibit Calu-6 proliferation in an IGF-independent manner and suggest that this enhanced potency might be because of the induction of SSR/DR dimerization. The Calu-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA on regulation of cell growth and to characterize the interaction between SSR and DR.

Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study

“…After 3 days, the culture medium was collected for hormone determination, and replaced by DME medium containing D-valine (Metachem, London, UK), 10 5 U/l penicillin, 1% FCS. The use of D-valine in the culture medium suppresses the proliferation of any remaining contaminating fibroblasts (Renner et al 1994 (Koper et al 1990, Florio et al 1992, Renner et al 1994, Ferone et al 2005.…”

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

“…EGFR: epidermal growth factor receptor; VEGFR2: vascular endothelial growth factor receptor 2; IGF1R: insulin-like growth factor 1 receptor; SSTR: somatostatin receptors; SOS: save our souls; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinosital biphosphate 2; PIP3: phosphatidylinosital biphosphate 3; PTEN: phosphatase and tensin homolog; MEK: methyl ethyl ketone; ERK: extracellular signal-regulated kinase ; AKT: protein kinase B; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase glucagonomas, and VIPomas (80-100%). [27,28] However, insulinomas express SSTR in 50-70% of cases, showing a prevalence of SSTR5 mRNA expression that is positively correlated with aggressive pathological characteristics. [29] SSTR2 is usually expressed in NENs, and its loss could be highly correlated with the dysregulation of tumor proliferation, consequently promoting tumor growth.…”

Antitumor effects of somatostatin

“…Such compounds have an enhanced potency in suppressing GH and PL release by cultured GH-secreting human adenomas compared to that of the individual sst2 and D2 receptor analogs, either used individually or combined. In addition, these chimeric analogs inhibit cell proliferation of the non-small-cell lung cancer cell Page 12 of 22 A c c e p t e d M a n u s c r i p t 12 line Calu-6, which expresses sst2, sst5 and D2R with higher potency and efficacy than sst2 and D2 receptor analogs (Ferone et al, 2005). Recent studies show that BIM23A760 can also inhibit ECL cell proliferation with similar potency but with higher efficacy than lanreotide and D2R analog (Kidd et al, 2007).…”