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Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease

Castillo, Victor and Theodoropoulou, Marily and Stalla, Johanna and Gallelli, Maria Florencia and Cabrera-Blatter, Maria Fernanda and Haedo, Mariana R and Labeur, Marta and Schmid, Herbert and Stalla, Günter K and Arzt, Eduardo (2010) Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease. Neuroendrocrinology, 94 (2). pp. 124-136. ISSN 0028-3835

Abstract

Canines have become in vivo models to test the pharmacological treatment of corticotrophinomas because they frequently develop Cushing’s disease in a spontaneous manner, due to ACTH-producing pituitary adenomas. SOM230 (Pasireotide) is a somatostatin (SRIF) analog that was developed a few years ago and has the distinctiveness of being a multiligand to the SSTR2 receptor subtype, which is related to mitogenic signaling pathways, and SSTR5, which is mainly related to the synthesis of POMC-ACTH. Both AtT20 and canine tumoral corticotrophinoma cells express high levels of SSTR2 and low levels of SSTR5. The objective of this study was to evaluate whether SOM230 controls, both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing’s disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months treatment followed by a two month rest period). A significant decrease in ACTH, urinary free cortisol, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, with no collateral effects. AtT20 cells treated with SOM230 suppressed POMC promoter activity through SSTR2, via the G1-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230 inhibits ACTH synthesis and cellular mitosis through SSTR2, therefore controlling Cushing’s disease in the dogs that received the treatment, thus indicating that SOM230 has a potential therapeutic use in humans suffering Cushing’s disease.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On author or institutional server; Publisher's version/PDF cannot be used
Keywords: SOM230, Cushing, Corticotrophs
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3018

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