Inhibition of endothelial proliferation by the somatostatin analogue SOM230

Adams, Robyn L.; Adams, Ian; Lindow, Stephen W.; Atkin, Stephen L.

doi:10.1111/j.1365-2265.2004.02098.x

Cited by 34 publications

(28 citation statements)

References 34 publications

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“…The high expression levels of SSTR2 in GH3 cells may explain the higher efficacy of the SSTR2 preferring agonist octreotide in our rat cells. SOM230 inhibits cell proliferation at concentrations of 10 K7 and 10 K6 M, but not at concentrations 10 K8 and 10 K9 M in human umbilical vein endothelial cells expressing SSTR1, -2 and -5 (45). Octreotide was only effective at a 10 K6 M dose in a recent in vitro study (34), again suggesting that the pharmacological data do not always translate into efficacy in cell systems under the same conditions.…”

Section: Discussionmentioning

confidence: 96%

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

et al. 2006

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Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3 H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

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Section: Discussionmentioning

confidence: 96%

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

et al. 2006

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“…In contrast, in breast cancer, sst 2 mRNA expression was significantly higher in low-proliferating (as measured using Ki-67) breast cancers (47). Note that in an endothelial cell line model (HUVEC) sst other than sst2 and sst3 appears important in controlling proliferation as demonstrated by the ability of the multivalent ligand SOM230, but not octreotide, to inhibit proliferation and this did not appear to be mediated via sst 3 as only sst 1 , sst 2 and sst 5 were detected using RT-PCR and western blotting (48). SOM230 or other specific sst 2 -sst 5 or sst 2 -D 2 agonists may thus represent suitable candidates as potential anti-angiogenic and anti-proliferating drugs.…”

Section: Discussionmentioning

confidence: 99%

The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies

O’Toole¹,

Saveanu²,

Couvelard³

et al. 2006

eur j endocrinol

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Objective: Somatostatin (sst) are present in the majority of gastro-entero-pancreatic (GEP) tumours. Effects of somatostatin receptor (sst) analogues are partial and of limited duration. Cell lines derived from GEP express dopaminergic receptors D 2 . New chimeric analogues simultaneously recognising sst 2 and sst 5 or sst 2 and D 2 have additive effects in inhibition of GH and prolactin secretion in pituitary adenomas. Our aim was to quantify the expression of sst and D 2 mRNA in human GEP tumours. Design and methods: mRNA expression of sst 1 , sst 2 , sst 3 and sst 5 as well as D 2 , was analysed using realtime PCR (TaqMan probe) in a series of 35 patients with GEP tumours (pancreas (nZ19) and intestinal (nZ16)). Levels of expression were compared with a group of 13 somatotroph adenomas. Results: All GEP tumours express sst 1 , sst 2 and D 2 . Expression of sst 3 and sst 5 was observed in 89 and 76% of tumours respectively with highly variable levels. sst 2 mRNA expression was higher in nonfunctional tumours (P!0.009) and sst5 was higher in pancreatic than in intestinal tumours (P!0.02). Whereas sst 2 levels were similar between GEP and somatotroph tumours, levels of sst 5 and D 2 were higher in the former (394.9G156.1!10 K2 vs 69.7G19.5!10 -2 copy/copy b-Gus (P!0.0036) and 519.6G121.2!10 K2 vs 50.0G21.6!10 -2 copy/copy b-Gus (P!0.0001) respectively). In small tumours (!30 mm), sst 2 density appeared as a crucial parameter in somatostatin receptor scintigraphy results, whereas in big tumours, a consistent bias in SRS results was introduced by the size. In pancreatic GEP, high-level sst 3 expression was found in tumours with more active angiogenesis (higher microvessel density and vascular endothelial growth factor expression (P!0.03)). Conclusions: GEP tumours co-express sst 2 and D 2 in 100% of cases and sst 5 in 89% thus supporting the testing of bi-specific agonists (sst 2 /sst 5 or sst 2 /D 2 ) in these tumours.European Journal of Endocrinology 155 849-857

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“…Moreover, neither of the SAs was able to modify cellular viability or induce cell death. Thus, octreotide and SOM230 are probably and their anti-angiogenic properties 24,29,30 should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Expression of Somatostatin Receptors in Human Melanoma Cell Lines: Effect of Two Different Somatostatin Analogues, Octreotide and SOM230, on Cell Proliferation

Martínez-Alonso¹,

Llecha²,

Mayorga

et al. 2009

J Int Med Res

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Inhibition of endothelial proliferation by the somatostatin analogue SOM230

Abstract: The pan SST analogue SOM230 inhibits proliferation of HUVECs, which are unaffected by Octreotide. SOM230 may thus represent a suitable candidate drug for antiangiogenic therapy.

Cited by 34 publications

References 34 publications

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies

Expression of Somatostatin Receptors in Human Melanoma Cell Lines: Effect of Two Different Somatostatin Analogues, Octreotide and SOM230, on Cell Proliferation

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