title: Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease.
abstract: SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. 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 of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G(i) α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease.
authors.affiliation: Unidad de Endocrinología, Hospital Escuela, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Victor
authors.initials: V
authors.lastname: Castillo
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: Johanna
authors.initials: J
authors.lastname: Stalla
authors.forename: Maria Florencia
authors.initials: MF
authors.lastname: Gallelli
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Cabrera-Blatter
authors.forename: Mariana R
authors.initials: MR
authors.lastname: Haedo
authors.forename: Marta
authors.initials: M
authors.lastname: Labeur
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Schmid
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis* / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D052680:Corticotrophs / Q000187:drug effects* / Q000378:metabolism*; D003404:Creatinine / Q000652:urine; D004285:Dogs; D005260:Female; D006854:Hydrocortisone / Q000652:urine; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D047748:Pituitary ACTH Hypersecretion / Q000378:metabolism* / Q000473:pathology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D000521:alpha-MSH / Q000097:blood
chemical_list: D001786:Blood Glucose; D014280:Triglycerides; D013004:Somatostatin; D000521:alpha-MSH; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; C517782:pasireotide; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D006854:Hydrocortisone