Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia

Abstract

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to adrenocorticotropin hormone (ACTH) - independent Cushing’s syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP–dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with Celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1,500 mg/kg Celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, Celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, Celecoxib caused histological changes that reversed, at least in part, BAH and this was associated with a reduction of corticosterone levels.

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

“…It was recently suggested that celecoxib, an inhibitor of the prostaglandin synthesizing enzyme cyclooxygenase-2, could be an interesting therapeutic alternative. In an adrenal cortex-specific PRKAR1A knockout mouse model (AdKO mice), Liu et al [32] evaluated the potential of celecoxib in vivo to prevent the onset of PPNAD. After 9 months of treatment with celecoxib, AdKO mice showed no sign of bilateral adrenal hyperplasia and had significantly lower plasmatic cortisol levels compared to untreated AdKO controls.…”

The Impact of Protein Supplementation Targeted at Improving Muscle Mass on Strength in Cancer Patients: A Scoping Review

“…Data from a different cohort of cancer patients at low risk of malnutrition did not show any effects of protein supplementation up to 50 g/day on muscle strength [ 37 ]. However, it should be noted that, despite the low risk of malnutrition, this population underwent androgen deprivation therapy, which notably exerts profound adverse effects on muscle mass with less clear effects on muscle strength [ 25 ]. Overall, it seems that when anabolic/anticatabolic interventions are applied alone or in association with dietary proteins, their effects overcome those of protein supplementation alone [ 37 , 38 , 39 ], without any additional synergistic contribution due to the addition of dietary proteins.…”

“…It should also be noted that while in some groups of individuals, e.g., elderly cancer patients, it may be almost impossible to separate the two conditions, in younger patients the prevalence of sarcopenia and dynapenia may depend on cancer type [ 24 ] and treatment. This is especially true when considering therapies that notably affect muscle mass and strength, such as hormone therapy [ 25 ]. From a clinical standpoint, dynapenia is very relevant to daily practice, as low muscle strength predicts poor physical performance and sarcopenia-related outcomes, including disability and mortality.…”

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

“…Starting from the study by Liu and coworkers (2013), who firstly reported the mutations in follicular cell-derived thyroid cancers, a relevant body of research has been performed by 3 leading groups and by the TCGA, focusing on prevalence and possible prognostic implications of TERT promoter mutations in thyroid cancer (Agrawal et al 2014, Melo et al 2014, Xing et al 2014b. Recently, a comprehensive meta-analysis summarising all available data has been published (Liu & Xing 2016). Although mutations were more frequent in less differentiated tumours, a relevant portion of DTC was involved (11.3% (4.5-25.5) of PTC and 17.1% (13.8-36.4) of FTC).…”

“…Particularly, strong evidence has been achieved about the deleterious prognostic effect related to this combination. Xing and his team were the first researchers to demonstrate that simultaneous occurrence of BRAF V600E and the TERT promoter mutation C228T, which is the most largely detected in DTC (Liu & Xing 2016), is more strongly associated to high-risk clinico-pathological features and to the development of tumour recurrence (Fig. 4A), compared with the presence of one of the mutations separately (Xing et al 2014b).…”