Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

Zatelli, Maria Chiara; Piccin, Daniela; Tagliati, Federico; Ambrosio, Maria Rosaria; Bondanelli, Marta; Cimino, Vincenzo; Bianchi, Antonio; Schmid, Herbert; Scanarini, M.; Pontecorvi, Alfredo; Marinis, Laura De; Maira, Giulio; Uberti, Ettore C. degli

doi:10.1677/erc-06-0026

Cited by 108 publications

(64 citation statements)

References 36 publications

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“…Pasireotide also inhibits IGF-1 action and induces apoptosis in mammary gland through a non-pituitary mechanism in intact and hypophysectomized female rats (Ruan et al, 2006). In additition, Pasireotide inhibits VEGF secretion and cell viability in human non-functioning pituitary adenomas primary cultures, and suppresses cell proliferation and ACTH secretion in primary cultures of human corticotroph tumors (Batista et al, 2006;Zatelli et al, 2007). These results support the hypothesis that pasireotide may have potential in the treatment of these tumors.…”

Section: Novel Somatostatin Analogs With Anti-tumor Capacitysupporting

confidence: 60%

“…These growth factors are secreted by tumor cells as well as by stroma cells and stimulate endothelial and smooth muscle cell proliferation and migration, which are important processes in angiogenesis. In various human cellular models such as glioma cell lines, retinal pigment epithelial cells or non-functioning pituitary adenoma, somatostatin or analogs inhibit VEGF synthesis at the protein and mRNA levels (Mentlein et al, 2001;Sall et al, 2004;Zatelli et al, 2007). Octreotide inhibits tumor expression of VEGF as well as VEGF serum level in colorectal cancer patients (Cascinu et al, 2001).…”

Section: Indirect Antitumor Effects Of Somatostatinmentioning

confidence: 99%

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Antitumor effects of somatostatin

Pyronnet

Bousquet

Najib

et al. 2008

Molecular and Cellular Endocrinology

159

118

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SummarySince its discovery three decades ago as an inhibitor of GH release from the pituitary gland, somatostatin has attracted much attention because of its functional role in the regulation of a wide variety of physiological functions in the brain, pituitary, pancreas, gastrointestinal tract, adrenals, thyroid, kidney and immune system. In addition to its negative role in the control of endocrine and exocrine secretions, somatostatin and analogs also exert inhibitory effects on the proliferation and survival of normal and tumor cells. Over the past 15 years, studies have begun to reveal some of the molecular mechanisms underlying the antitumor activity of somatostatin. This review covers the present knowledge in the antitumor effect of somatostatin and analogs and discusses the perspectives of novel clinical strategies based on somatostatin receptor sst2 gene transfer therapy.

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Section: Novel Somatostatin Analogs With Anti-tumor Capacitysupporting

confidence: 60%

Section: Indirect Antitumor Effects Of Somatostatinmentioning

confidence: 99%

Antitumor effects of somatostatin

Pyronnet

Bousquet

Najib

et al. 2008

Molecular and Cellular Endocrinology

159

118

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“…Among the currently available SSAs, pasireotide represents the most promising compound, given its 11-fold higher functional activity on SSTR3 than octreotide and lanreotide. Evidence obtained during in vitro studies that pasireotide inhibits the viability of NFPAs in primary cultures (Zatelli et al 2007) further supports the hypothesis that SSTR3 is a suitable target for treatment. Indeed, the anti-proliferative effect of pasireotide on NFPAs cultures, in addition to a suppressive action on VEGF secretion (Zatelli et al 2007), may also be mediated by pathways downstream of SSTR3.…”

Section: Discussionmentioning

confidence: 76%

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

Lee¹,

Lupp²,

Mendoza³

et al. 2014

Endocrine-Related Cancer

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Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P!0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.

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“…These studies have shown that SSTR2-aimed SSAs are usually ineffective (Kopczak et al 2014, Peverelli et al 2015, although there is high expression of SSTR3 and SSTR2 and lower expression of SSTR5 (Taboada et al 2007, Zatelli et al 2007, Florio et al 2008, Tateno et al 2009, Hofland et al 2010, Lee et al 2015, Ibáñez-Costa et al 2016). An in vitro study which used individual and combined SSTR 235:3 agonists suggested that SSTR1 agonists might be useful (Zatelli et al 2004), and moreover, that pasireotide may reduce cell viability in vitro via the inhibition of VEGF (Zatelli et al 2007). Indeed, the use of pasireotide was proposed for non-functioning pituitary adenoma patients (Colao et al 2008), as it has been reflected in two clinical trials (NCT01620138 and NCT01283542; https://clinicaltrials.gov).…”

Section: Somatostatin Analogues and Pituitary Adenomasmentioning

confidence: 99%

AIP and the somatostatin system in pituitary tumours

Ibáñez‐Costa

Korbonits

2017

Journal of Endocrinology

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Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

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Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

Abstract: Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF

Cited by 108 publications

References 36 publications

Antitumor effects of somatostatin

Antitumor effects of somatostatin

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

AIP and the somatostatin system in pituitary tumours

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