Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds

The antisecretory effects of somatostatin (SRIH) and its analogs are widely recognized and provide the basis for treatment of hormonal hypersecretion in patients with pituitary adenomas, especially in the settings of acromegaly. Dopamine (DA) agonists have also been used for medical treatment of prolactin and/or GH hypersecretion, and recent evidence points to an even greater antisecretory effect for a chimeric molecule, having high affinity for both SRIH and DA receptors. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the antiproliferative effects of SRIH and its analogs, of DA and chimeric compounds on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drug

IGF-I influences everolimus activity in medullary thyroid carcinoma

Context: Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells. It has been previously demonstrated that insulin-like growth factor I (IGF-I) protects MTC from the effects of antiproliferative drugs. Everolimus, an mTOR inhibitor, has shown potent antiproliferative effects in a human MTC cell line, TT, and in two human MTC primary cultures. Objective: To verify whether IGF-I may influence the effects of everolimus in a group of human MTC primary cultures. Design: We collected 18 MTCs that were dispersed in primary cultures, treated without or with 10 nM-1 mu M everolimus and/or 50 nM IGF-I. Cell viability was evaluated after 48 h, and calcitonin (CT) secretion was assessed after a 6 h incubation. IGF-I receptor downstream signaling protein expression profile was also investigated. Results: Everolimus significantly reduced cell viability in eight MTC [by similar to 20%; P < 0.01 vs. control; everolimus-responders (E-R) MTCs], while cell viability did not change in 10 MTCs [everolimus-non-responders (E-NR) MTCs]. In E-R MTCs, IGF-I blocked the antiproliferative effects of everolimus that did not affect CT secretion, but blocked the stimulatory effects of IGF-I on this parameter. IGF-I receptor downstream signaling proteins were expressed at higher levels in E-NR MTC as compared to E-R MTCs. Conclusion: IGF-I protects a subset of MTC primary cultures from the antiproliferative effects of everolimus and stimulates CT secretion by an mTOR mediated pathway that, in turn, may represent a therapeutic target in the treatment of aggressive MTCs

Targeting protein kinase C by Enzastaurin restrains proliferation and secretion in human pancreatic endocrine tumors

Dysregulation of the protein kinase C (PKC) signaling pathway has been implicated in tumor progression. In this study, we investigate the effects of a PKC inhibitor, Enzastaurin, in human pancreatic neuroendocrine neoplasms (PNN) primary cultures and in the human pancreatic endocrine cancer cell line, BON1. To this aim six human PNN dispersed in primary cultures and BON1 cells were treated without or with 1–10 μM Enzastaurin and/or 100 nM IGF1 in the presence or absence of serum. Cell viability and apoptosis were evaluated after 48–72 h; Chromogranin A (CgA) and/or insulin secretion was assessed after 6 h of incubation. PKC expression was investigated by immunofluorescence and western blot. We found that Enzastaurin significantly reduced human PNN primary culture cell viability, as well as CgA and insulin secretion. Moreover, in the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 μM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin. In addition, Enzastaurin blocked the stimulatory effect of IGF1 on cell proliferation, and reduced CgA expression and secretion in BON1 cells. Two different PKC isoforms are expressed at different levels and have partially different subcellular localization in BON1 cells. In conclusion, Enzastaurin reduces cell proliferation by inducing apoptosis, with a mechanism likely involving GSK3β signaling, and inhibits secretory activity in PNNin vitromodels, suggesting that Enzastaurin might represent a possible medical treatment of human PNN

Terapia con GH in età adulta: problemi aperti

L''efficacia della terapia sostitutiva con Gh in età adulta è ampiamente dimostrata. Nell'articolo si discutono problemi tuttora aperti, quali le ripercussioni sul metabolismo glucidico ed il rischio di recidiva del tumore ipofisarioo l'insorgenza di seconda neoplasia

Secrezioni ormonali ectopiche

Il capitolo descrive le principali sindromi da secrezione ormonale ectopica, illustrando le modalità diagnostiche e terapeutich

Effect of somatostatin on growth hormone and prolactin response to dermorphin in man

Effect of somatostatin on growth hormone and prolactin response to dermorphin in ma

The effects of dermorphin on the endocrine system in man

This paper summarizes the results of our recent studies in a group of healthy subjects on the endocrine effects of the new potent opioid peptide, dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), originally isolated from amphibian skin. Intravenous infusion (5.5 μg/kg/min for 30 min) of dermorphin (D) significantly increased plasma levels of prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and renin activity (PRA), but decreased plasma levels of cortisol. D produced a small decrease in ACTH, and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone (N) suppressed the PRL and TSH response to D, blunted the D-induced GH and PRA increase, and completely prevented the D-induced plasma cortisol decrease, but enhanced plasma cortisol and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that: (1) D, a new opioid peptide, can stimulate PRL, GH, and TSH release in humans; (2) D increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; (3) D suppresses plasma cortisol levels, by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis. © 1985

Strategies to use microRNAs as therapeutic targets

Abstract MicroRNAs (miRNAs) are non-coding RNAs generated from endogenous hairpin-shaped transcripts that powerfully regulate gene expression at post-transcriptional level. Each miRNA is capable to regulate the expression levels of hundreds of transcripts and each mRNA may have more than one miRNA recognition sequence. There is emerging evidence that deregulation of miRNA expression leads to the alteration of pivotal physiological functions contributing to the development of diseases and neoplasms, including pituitary adenoma. This review is aimed at providing the up-to-date knowledge concerning deregulated miRNAs of pituitary tumors and their functions. In order to take stock, pituitary tumors have been sub-divided in different classes on the basis of tumor features (histotype, dimension, aggressiveness). The overview takes full consideration of the recent advances in miRNAs role as potential therapeutics and biomarkers