Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro

Lesche, Sarah; Lehmann, Dirk J.; Nagel, Falko; Schmid, Herbert; Schulz, Stefan

doi:10.1210/jc.2008-1919

Cited by 154 publications

(123 citation statements)

References 28 publications

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“…Similar results were obtained in mice and rats (results not shown). Thus, pasireotide activates the somatostatin receptor SSTR2A without causing its rapid internalization, indicating that agonist-selective effects of octreotide and pasireotide also occur in vivo (32,33).…”

Section: Resultsmentioning

confidence: 99%

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Imhof¹,

Glück²,

Gajda³

et al. 2011

Arthritis & Rheumatism

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Objective. Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties. However, it is not known which of the 5 somatostatin receptor subtypes (SSTRs 1-5) is involved in these actions. The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide (SOM230) in a mouse model of antigen-induced arthritis (AIA). Methods. Studies were performed in SSTR2-deficient mice (SSTR2 -/-) and their wild-type littermates (SSTR2 ؉/؉). The expression of SSTR1, SSTR2A, SSTR3, and SSTR5 in dorsal root ganglia was examined by immunohistochemistry.Results. Untreated SSTR2 -/-mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in SSTR2 ؉/؉ mice. In wild-type mice, both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone. In SSTR2 -/-mice, the antiinflammatory effects of both octreotide and pasireotide were completely abrogated. Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions. In addition, both octreotide and pasireotide reduced inflammatory hyperalgesia. The antinociceptive actions of octreotide were abolished in SSTR2 -/-mice, but those of pasireotide were retained. In dorsal root ganglia of naive wild-type mice, only SSTR1 and SSTR2A, but not SSTR3 or SSTR5, were detected in a subset of small-and mediumdiameter neurons.Conclusion. Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the SSTR2 receptor. In addition, we identified the SSTR1 receptor as a novel pharmacologic target for somatostatinmediated peripheral analgesia in inflammatory pain.

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Section: Resultsmentioning

confidence: 99%

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Imhof¹,

Glück²,

Gajda³

et al. 2011

Arthritis & Rheumatism

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“…In two recent in vitro studies octreotide and pasireotide (SOM 230) have been demonstrated to modulate sst 2A receptor phosphorylation and trafficking in a clearly distinct manner, despite their approximately similar binding affinity to this SSTR subtype (Poll et al 2010). Pasireotide appeared to be more potent than octreotide in inducing internalization and signaling of human sst 3 and sst 5 receptors (Lesche et al 2009). The observed behavior of SOM 230 as only a partial agonist of sst 2 sheds light on the importance of the agonist-induced receptor conformation in affecting receptor signaling and regulation, more than binding affinity alone.…”

Section: Ss and Da Analogs Treatment In Endocrine Tumorsmentioning

confidence: 99%

“…Since SSTR and D 2 -like receptors mainly exert inhibitory functions, medical therapies targeting these receptors with selective agonists have been developed for the treatment of a number of neuroendocrine disorders. In the last decades, the knowledge on the pathophysiology of these two families of GPCRs in NET has progressively increased due to the new insights in receptor dimerization, internalization, and trafficking (Hofland & Lamberts 2003, Ferone et al 2009, Lesche et al 2009, Poll et al 2010. Moreover, the recent availability and use of novel selective and universal SSAs and DA agonists, as well as the chimeric SS/DA compounds, has shed light on the potential role of SSTR and D 2 as combined targets for biotherapy in NET.…”

Section: Introductionmentioning

confidence: 99%

The role of somatostatin and dopamine D2 receptors in endocrine tumors

Gatto¹,

Hofland²

2011

Endocrine-Related Cancer

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Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D 2 receptor (D 2 ) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D 2 as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D 2 pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.

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“…Like the PET tracer 68 Ga-DOTATATE, octreotide binds to SSTR subtype 2, where it acts as an agonist. This common molecular target of the medication and the tracer could reduce the specific PET signal by simple competition or by evoking internalization of SSTR subtype 2 receptors, as is seen after treatment with octreotide in vitro (8)(9)(10)(11)). An additional potential confounding factor is suggested by the observation that SSTR expression was induced by incubation of pituitary cells in culture with a somatostatin analog (12).…”

mentioning

confidence: 99%

Treatment with Octreotide Does Not Reduce Tumor Uptake of ⁶⁸Ga-DOTATATE as Measured by PET/CT in Patients with Neuroendocrine Tumors

Haug¹,

Rominger²,

Mustafa³

et al. 2011

J Nucl Med

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Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro

Cited by 154 publications

References 28 publications

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

The role of somatostatin and dopamine D2 receptors in endocrine tumors

Treatment with Octreotide Does Not Reduce Tumor Uptake of ⁶⁸Ga-DOTATATE as Measured by PET/CT in Patients with Neuroendocrine Tumors

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Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro

Cited by 154 publications

References 28 publications

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

The role of somatostatin and dopamine D2 receptors in endocrine tumors

Treatment with Octreotide Does Not Reduce Tumor Uptake of 68Ga-DOTATATE as Measured by PET/CT in Patients with Neuroendocrine Tumors

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Treatment with Octreotide Does Not Reduce Tumor Uptake of ⁶⁸Ga-DOTATATE as Measured by PET/CT in Patients with Neuroendocrine Tumors