Search Results (19)

Background. Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer. Methods/Results. We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40–50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis. Conclusion. The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy. Full article

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial–mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment. Full article

Alzheimer’s disease imposes an increasing burden on aging Western societies. The disorder most frequently appears in its sporadic form, which can be caused by environmental and polygenic factors or monogenic conditions of incomplete penetrance. According to the authors, in the majority of cases, Alzheimer’s disease represents an aggravated form of the natural aging of the central nervous system. It can be characterized by the decreased elimination of amyloid β_1–42 and the concomitant accumulation of degradation-resistant amyloid plaques. In the present paper, the dysfunction of neuropeptide regulators, which contributes to the pathophysiologic acceleration of senile dementia, is reviewed. However, in the present review, exclusively those neuropeptides or neuropeptide families are scrutinized, and the authors’ investigations into their physiologic and pathophysiologic activities have made significant contributions to the literature. Therefore, the pathophysiologic role of orexins, neuromedins, RFamides, corticotrope-releasing hormone family, growth hormone-releasing hormone, gonadotropin-releasing hormone, ghrelin, apelin, and natriuretic peptides are discussed in detail. Finally, the therapeutic potential of neuropeptide antagonists and agonists in the inhibition of disease progression is discussed here. Full article

The development of resistance remains the primary challenge in treating castration-resistant prostate cancer (CRPC). GHRH receptors (GHRH-R), which are coupled to G-proteins (GPCRs), can mediate EGFR transactivation, offering an alternative pathway for tumour survival. This study aimed to evaluate the effects of the GHRH-R antagonist MIA-690, in combination with the EGFR inhibitor Gefitinib, on cell viability, adhesion, gelatinolytic activity, and the cell cycle in advanced prostate cancer PC-3 cells. The findings demonstrate a synergistic effect between MIA-690 and Gefitinib, leading to the inhibition of cell viability, adhesion, and metalloprotease activity. Cell cycle analysis suggests that both compounds induce cell cycle arrest, both individually and in combination. Furthermore, similar effects of the GHRH-R antagonist MIA-690 combined with Gefitinib were observed in PC-3 tumours developed by subcutaneous injection in athymic nude mice 36 days post-inoculation. These results indicate that combined therapy with a GHRH-R antagonist and an EGFR inhibitor exerts a stronger antitumor effect compared to monotherapy by preventing transactivation between EGFR and GHRH-R in CRPC. Full article

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment. Full article

GHRH regulates the secretion of GH from the anterior pituitary gland, previously associated with cancer progression and inflammation. An emerging body of evidence suggests that GHRHAnt support endothelial barrier function, but the mechanisms mediating these events are not completely understood. In the present study, it is demonstrated that the GHRHAnt JV-1-36 counteracts barrier dysfunction due to LPS or LTA treatment in HUVECs, utilizing the Dextran–FITC assay. Moreover, it is shown in BPAECs that these bacterial toxins increase ROS generation, and that this effect is counteracted by JV-1-36, which reinstates the redox balance. The possible involvement of NEK2 in the beneficial activities of GHRHAnt in IFN-γ- and LPS-triggered hyperpermeability was also assessed, since that kinase is involved in inflammatory responses. NEK2 was increased in the inflamed cells, and JV-1-36 counteracted those endothelial events. Our data support the beneficial effects of GHRHAnt in toxin-induced endothelial injury. Full article

In aquaculture, stress can negatively affect fish growth. For years, the cortisol hormone has been thought to play both glucocorticoid and mineralocorticoid functions. Nevertheless, recent research has suggested that 11-deoxycorticosterone (DOC) released during stress could contribute to cortisol actions, though this process is still misunderstood. Here, we evaluated the DOC effects on physiological and early transcriptional responses by RNA-seq. Juvenile rainbow trout were treated with DOC and/or glucocorticoids (mifepristone) or mineralocorticoid (eplerenone) receptor antagonists. Subsequently, plasma was collected, and cDNA libraries were generated from the gills of vehicle (control), DOC, mifepristone, mifepristone with DOC, eplerenone, and eplerenone with DOC groups. Calcium and phosphate levels in plasma were changed. Results revealed 914 differentially expressed transcripts (DETs) induced by DOC compared with control, mainly associated with sodium ion transmembrane transport, gluconeogenesis, negative regulation of transmembrane transport, and activation of innate immune response. DOC versus eplerenone with DOC comparison displayed 444 DETs related to cell-cell junction organization, canonical glycolysis, positive regulation of immune response, and potassium ion transport. Conversely, no DETs were detected in DOC versus mifepristone with DOC comparison. These data suggest that DOC has a relevant role in gill stress response and ion transport, which is differentially regulated by mineralocorticoid receptors. Full article

The reasons initiating insulin resistance are not identified. Various metabolic derailments have been characterized. These are the outcome and not the initiation of insulin resistance. In animal models of type 2 diabetes and hypertension, a decreased hormonal stimulation of the synthesis of the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP) was determined. The resultant imbalance of the action of cyclic AMP and cyclic PIP shifts metabolic regulation to the dominance of catabolism and a decrease in imperative anabolism. This dominance develops gradually since the more cyclic AMP dominates, the more the synthesis of cyclic PIP will be inhibited. Vanishing actions of cyclic PIP are its 10-fold activation of glucose uptake in adipocytes, its inhibition of insulin release from pancreatic β-cells, its inhibition of PKA and its 7-fold activation of protein ser/thr phosphatase. Reduced synthesis of cyclic PIP results from (a) decreased substrate availability, (b) long-time elevated cyclic AMP levels resulting from stress overloads and (c) aging and the gradual decrease in the synthesis of hormones which likely maintain mechanisms that stimulate cyclic PIP synthesis. The need is to discover which hormones, such as growth hormone, insulin-like growth factor-1, dehydroepiandrosterone, and testosterone, are involved in maintaining the stimulation of cyclic PIP synthesis. Full article

Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the endocrine system and mood disorders. In this context, the effects induced by MIA-602 were also analyzed in comparison to vehicle-treated mice with GH deficiency due to generalized ablation of the GHRH gene (GHRH knock out (GHRHKO)). We show that the chronic subcutaneous administration of MIA-602 to wild type (+/+) mice, as well as generalized ablation of the GHRH gene, is associated with anxiolytic and antidepressant behavior. Moreover, immunohistochemical and Western blot analyses suggested an evident activation of Nrf2, HO1, and NQO1 in the prefrontal cortex of both +/+ mice treated with MIA-602 (+/+ MIA-602) and homozygous GHRHKO (−/− control) animals. Finally, we also found significantly decreased COX-2, iNOS, NFkB, and TNF-α gene expressions, as well as increased P-AKT and AKT levels in +/+ MIA-602 and −/− control animals compared to +/+ mice treated with vehicle (+/+ control). We hypothesize that the generalized ablation of the GHRH gene leads to a dysregulation of neural pathways, which is mimicked by GHRH antagonist treatment. Full article

Ghrelin is an orexigenic neuropeptide that is known for stimulating the release of growth hormone (GH) and appetite. In addition, ghrelin has been implicated in addiction to drugs such as nicotine. Nicotine is the principal psychoactive component in tobacco and is responsible for the reward sensation produced by smoking. In our previous in vitro superfusion studies, it was demonstrated that ghrelin and nicotine stimulate equally the dopamine release in the rat amygdala, and ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. However, less attention was paid to the actions of ghrelin and nicotine in the bed nucleus of the stria terminalis (BNST). Therefore, in the present study, nicotine and ghrelin were superfused to the BNST of male Wistar rats, and the dopamine release from the BNST was measured in vitro. In order to determine which receptors mediate these effects, mecamylamine, a non-selective nicotinic acetylcholine receptor (nAchR) antagonist, and GHRP-6, a selective growth hormone secretagogue receptor (GHS-R1A) antagonist, were also superfused to the rat BNST. Nicotine significantly increased the release of dopamine, and this effect was significantly inhibited by mecamylamine. Ghrelin increased dopamine release even more significantly than nicotine did, and this effect was significantly inhibited by GHRP-6. Moreover, when administered together, ghrelin significantly amplified the nicotine-induced release of dopamine in the BNST, and this additive effect was reversed partly by mecamylamine and partly by GHRP-6. Therefore, the present study provides a new base of evidence for the involvement of ghrelin in dopamine signaling implicated in nicotine addiction. Full article

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H₂O₂-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers. Full article

Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM. Full article

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various tumors, including endometrial carcinomas (EC). However, tumoral receptors that mediate the antiproliferative effects of GHRH antagonists in human ECs have not been fully characterized. In this study, we investigated the expression of mRNA for GHRH and splice variants (SVs) of GHRH receptors (GHRH-R) in 39 human ECs and in 7 normal endometrial tissue samples using RT-PCR. Primers designed for the PCR amplification of mRNA for the full length GHRH-R and SVs were utilized. The PCR products were sequenced, and their specificity was confirmed. Nine ECs cancers (23%) expressed mRNA for SV1, three (7.7%) showed SV2 and eight (20.5%) revealed mRNA for SV4. The presence of SVs for GHRH-Rs could not be detected in any of the normal endometrial tissue specimens. The presence of specific, high affinity GHRH-Rs was also demonstrated in EC specimens using radioligand binding studies. Twenty-four of the investigated thirty-nine tumor samples (61.5%) and three of the seven corresponding normal endometrial tissues (42.9%) expressed mRNA for GHRH ligand. Our findings suggest the possible existence of an autocrine loop in EC based on GHRH and its tumoral SV receptors. The antiproliferative effects of GHRH antagonists on EC are likely to be exerted in part by the local SVs and GHRH system. Full article

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T₃ and T₄) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions. Full article

Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found to inhibit GHRH-induced secretion of pituitary GH in vitro and in vivo. However, the antitumor role of GHRH antagonists in PAs is largely unknown. Here, we show that the GHRH antagonists of MIAMI class, MIA-602 and MIA-690, inhibited cell viability and growth and promoted apoptosis in GH/prolactin-secreting GH3 PA cells transfected with human GHRH receptor (GH3-GHRHR), and in adrenocorticotropic hormone ACTH-secreting AtT20 PA cells. GHRH antagonists also reduced the expression of proteins involved in tumorigenesis and cancer progression, upregulated proapoptotic molecules, and lowered GHRH receptor levels. The combination of MIA-690 with temozolomide synergistically blunted the viability of GH3-GHRHR and AtT20 cells. Moreover, MIA-690 reduced both basal and GHRH-induced secretion of GH and intracellular cAMP levels. Finally, GHRH antagonists inhibited cell viability in human primary GH- and ACTH-PA cell cultures. Overall, our results suggest that GHRH antagonists, either alone or in combination with pharmacological treatments, may be considered for further development as therapy for PAs. Full article