Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo

Design: Cell viability, ACTH secretion (enzyme-linked immunosorbent assay), apoptosis, and gene expression profile were investigated on AtT-20 cells. In vivo efficacy was examined in an athymic nude mouse AtT-20 xenograft model. SAHA efficacy against human-derived corticotroph tumor (hCtT) (n = 8) was tested in vitro.Setting: National Institutes of Health.Intervention: SAHA (0.5 to 8 mM). Main Outcome Measures:AtT-20 and hCtT cell survival, in vitro/in vivo ACTH measurements.Results: SAHA (1 mM) reduced AtT-20 viability to 75% at 24 hours, 43% at 48 hours (analysis of variance; P = 0.002). Apoptosis was confirmed with elevated BAX/Bcl2 ratio and FACS. Intriguingly, early (3-hour) significant decline (70%; P , 0.0001) of secreted ACTH and diminished POMC transcription was observed with SAHA (1 mM). Microarray analysis revealed a direct association between liver X receptor alpha (LXRa) and POMC expression. Accordingly, SAHA reduced LXRa in AtT-20 cells but not in normal murine corticotrophs. Xenografted nude-mice tumor involution (126 6 33/160 6 35 vs 337 6 49 mm 3 ; P = 0.0005) was observed with 5-day intraperitoneal SAHA, with reversal of elevated ACTH (P , 0.0001). SAHA did not affect serum ACTH in nontumor mice. Lastly, we confirmed that SAHA (1 mM/24 h) decreased hCtT survival (78.92%; P = 0.0007) and ACTH secretion (83.64%; P = 0.03).Conclusion: Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/unremitting CD. (J Clin

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“…2(e)]. These results compare favorably with the effects of pasireotide in the reduction of ACTH secretion (approximately 10% at 24 hours) (30).…”

Section: Discussionsupporting

confidence: 55%

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease

Lü

Chatain

Bugarini

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…In previous in vitro and in vivo studies, pasireotide has also been associated with an anti-tumoral effect (12,44,45,46). A recent publication reporting the use of longacting pasireotide demonstrated that median tumor volume decreased by 17.8% and 16.3%, respectively, after 12 months of treatment with pasireotide at 10 or 30 mg/month in patients with Cushing's disease (14).…”

Section: Discussionmentioning

confidence: 98%

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Castellnou

Vasiljevic

Lapras

et al. 2020

Endocrine Connections

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Objective Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients. Design Retrospective cohort study. Methods Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations. Results SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4). Conclusion SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

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“…Lapatinib also decreased AtT-20 cell proliferation and induced DNA fragmentation in corticotroph tumor cells. These data suggest that the inhibitor would induce cell death in the tumor cells [18]. The ACTH levels in the medium might be less decreased, compared with cell proliferation.…”

Section: Discussionmentioning

confidence: 84%

“…Lapatinib also decreased tumor Pttg1 mRNA levels. In our previous study, tumor Pttg1 mRNA levels were decreased by SOM230, a multiligand somatostatin analog [18]. Pttg1 knockdown inhibits cell proliferation [25] and PTTG1 might thus be associated with inhibition of cell proliferation in corticotroph tumor cells.…”

Section: Discussionmentioning

confidence: 87%

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells

et al. 2019

Self Cite

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Cushing's disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing's disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease.

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Inhibitory effects of SOM230 on adrenocorticotropic hormone production and corticotroph tumor cell proliferation in vitro and in vivo

Cited by 17 publications

References 38 publications

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells

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