title: Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo.
abstract: Adrenocorticotropic hormone (ACTH) production by pituitary corticotroph adenomas is the main cause of Cushing's disease. A drug that targets pituitary ACTH-secreting adenomas would aid treatment of Cushing's disease. Octreotide, a somatostatin receptor type 2 (SSTR2)-preferring somatostatin analogue, has no effect on ACTH secretion in patients with Cushing's disease. The multiligand SOM230 (pasireotide) displays a much higher affinity for SSTR1 and SSTR5 than octreotide and suppresses ACTH secretion in cultures of human corticotroph tumors to a greater extent than octreotide. In the present in vitro and in vivo study, we determined the effect of SOM230 on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. SOM230 decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that SOM230 suppresses ACTH synthesis and secretion in corticotroph tumor cells. SOM230 also decreased cell proliferation and both cyclic adenosine monophosphate response element-binding protein and Akt phosphorylation in AtT-20 cells. SSTR5 knockdown inhibited the SOM230-induced decreases in cell proliferation. Fluorescence-activated cell sorting analyses revealed that SOM230 did not attenuate cell cycle progression. Tumor weight in mice xenografted with AtT-20 cells and treated with SOM230 was significantly lower than in AtT-20-xenografted control mice. SOM230 also significantly decreased plasma ACTH levels, and POMC and pituitary tumor transforming gene mRNA levels in the tumor cells. Thus, SOM230 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo.
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Murasawa
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; Department of Endocrinology, Metabolism, and Infectious Diseases, Hirosaki University School of Medicine & Hospital, 53 Hon-cho, Hirosaki, Aomori 036-8563, Japan. Electronic address: kkageyama@hkg.odn.ne.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kageyama
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugiyama
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishigame
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Niioka
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Daimon
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052680:Corticotrophs / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017481:Receptors, Somatostatin; D013004:Somatostatin; D011333:Pro-Opiomelanocortin; C094573:somatostatin receptor 5; D000324:Adrenocorticotropic Hormone; C517782:pasireotide; D051057:Proto-Oncogene Proteins c-akt
keywords: ACTH; Cushing’s disease; POMC; Pituitary tumor; Treatment