scholarly journals Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3950
Author(s):  
Iacopo Gesmundo ◽  
Giuseppina Granato ◽  
Antonio C. Fuentes-Fayos ◽  
Clara V. Alvarez ◽  
Carlos Dieguez ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Viability ◽  
Cancer Progression ◽  
Intracellular Camp ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Receptor ◽  
Ghrh Antagonists

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.

Effect of novel growth hormone-releasing hormone antagonists on growth of experimental renal cell carcinomas.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 469-469 ◽  
Author(s):  
Ferenc Rick ◽  
Luca Szalontay ◽  
Andrew Abi-Chaker ◽  
Norman L. Block ◽  
Gabor Halmos ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Lines ◽  
Renal Cell ◽  
Histological Evaluation ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Receptor ◽  
Ghrh Antagonists

469 Background: Although targeted therapy has improved the clinical outcome for patients with metastatic renal cell carcinoma (RCC), a complete response is rare and therapy has adverse effects. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. Herein, we investigate the effects of novel and highly potent antagonists of GHRH of MIA class on the growth of three RCC cell lines. Methods: The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The influence of GHRH antagonists MIA-602, MIA-604, MIA-606, and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at dose of 5µg daily in these three nude-mice xenograft models. Cell cycle parameters were analyzed by laser flow cytometry. Results: Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranged from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN cells with MIA-690 (10µM) led to a significant increase in number of cells with subG1DNA content, suggesting apoptosis. Conclusions: The effectiveness of the novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct inhibitory effects exerted through GHRH receptors. Biochemical and histological evaluation is needed to explore the mechanisms of action of GHRH antagonists in RCC.

scholarly journals Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

2019 ◽  
Vol 116 (6) ◽  
pp. 2226-2231 ◽  
Author(s):  
Tania Villanova ◽  
Iacopo Gesmundo ◽  
Valentina Audrito ◽  
Nicoletta Vitale ◽  
Francesca Silvagno ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Antagonists

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

Preclinical efficacy of growth hormone-releasing hormone antagonist MIA-602 for androgen-dependent and castration-resistant human prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 221-221
Author(s):  
Ferenc G. Rick ◽  
Cale D. Fahrenholtz ◽  
Maria I. Garcia ◽  
Norman L. Block ◽  
Andrew V. Schally ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Hormone ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Castration Resistant ◽  
Ghrh Antagonists

221 Background: Advanced hormone-sensitive prostate cancer (PCa) responds to androgen deprivation therapy (ADT). However, therapeutic options for castration-resistant disease are limited. As growth hormone-releasing hormone receptor (GHRH-R) and ligand GHRH are regulated in an autocrine fashion in PCa, GHRH-R inhibition represents a novel approach to PCa treatment. We investigated the effects of a new, highly potent GHRH antagonist, MIA-602, on growth of androgen-dependent and castration-resistant PCa cells in vitro/in vivo. Methods: All three cell lines used in this study expressed androgen receptors (ARs). 22Rv1 cells are castration-resistant and also express clinically relevant AR splice variants. LNCaP and VCaP lines are androgen dependent models that progress to castration resistance following ADT. Protein and mRNA levels of GHRH-R and its biologically active splice variant, SV1, were evaluated in cell lines and tumors by immunoblot and real-time RT-PCR. The influence of MIA-602 on cell proliferation and tumor formation was examined. Results: GHRH-R and SV1 were present in 22Rv1, LNCaP, and VCaP. LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared to 22Rv1. However, 22Rv1 expressed higher levels of SV1. Inhibition of GHRH-R using MIA-602 decreased cell proliferation in vitro of 22Rv1, LNCaP, and VCaP PCa cell lines respectively by 70.4%, 60.7% and 20.3% (P<0.05 for all). MIA-602 decreased 22Rv1 xenograft volumes in mice by 63% after 3 weeks of treatment. VCaP showed a substantial inhibition of xenograft growth following therapy with MIA-602 in vivo. MIA-602 effectively inhibited VCaP xenografts as a single agent or in combination with ADT by surgical castration. Conclusions: The effectiveness of the novel Miami class GHRH antagonist, MIA-602, in inhibiting growth of androgen-dependent and castration-resistant PCa models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists appear to be due to effects exerted through GHRH receptors on cancer cells and/or possibly by indirect mechanisms. Further investigations of GHRH antagonists for PCa treatment are warranted.

scholarly journals Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2331
Author(s):  
Chongxu Zhang ◽  
Tengjiao Cui ◽  
Renzhi Cai ◽  
Medhi Wangpaichitr ◽  
Mehdi Mirsaeidi ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Lung Physiology ◽  
Extracellular Signal ◽  
P21 Activated Kinase

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.

Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone

Cancer ◽  
2002 ◽  
Vol 95 (8) ◽  
pp. 1735-1745 ◽  
Author(s):  
Ryszard Braczkowski ◽  
Andrew V. Schally ◽  
Artur Plonowski ◽  
Jozsef L. Varga ◽  
Kate Groot ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Lines ◽  
Ewing Sarcoma ◽  
Growth Hormone Releasing Hormone ◽  
Sarcoma Cell ◽  
Inhibition Of Proliferation ◽  
Releasing Hormone

GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity

2020 ◽  
Vol 52 (05) ◽  
pp. 336-339 ◽  
Author(s):  
Nektarios Barabutis ◽  
Mohammad S. Akhter ◽  
Mohammad A. Uddin ◽  
Khadeja-Tul Kubra ◽  
Andrew V. Schally
Keyword(s):  
Growth Hormone ◽  
Anticancer Agents ◽  
Growth Hormone Releasing Hormone ◽  
Barrier Dysfunction ◽  
Microvascular Endothelium ◽  
Releasing Hormone ◽  
Ghrh Antagonists ◽  
Hormone Antagonists ◽  
The Brain

AbstractGrowth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H2O2-induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson’s and Alzheimer’s diseases.

Treatment of urinary bladder cancers by growth hormone-releasing hormone antagonists: A preclinical report.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 433-433
Author(s):  
Ferenc G. Rick ◽  
Petra Popovics ◽  
Norman L. Block ◽  
Jinlin He ◽  
Xian Yang Zhang ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Bladder Cancer ◽  
Urinary Bladder ◽  
Nude Mice ◽  
Splice Variant ◽  
Tumor Volume ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Antagonists

433 Background: Urinary bladder cancer is the fifth most frequent cancer diagnosed and among the most expensive cancers to treat in the United States. The management of muscle-invasive tumors presents a clinical challenge because of the toxicity and limitations in efficacy and durability of current therapeutic modalities. Novel therapeutic strategies for this disease are of paramount importance. Growth hormone-releasing hormone (GHRH) receptors and its splice variant were detected in a series of urothelial malignancies and GHRH has been shown to influence the growth of these tumors. Herein we evaluated the effect of GHRH antagonists on the growth of various experimental human urinary bladder cancers in vitro and in vivo in nude mice. Methods: We investigated the effects of several GHRH antagonists MIA 602, MIA 606 and MIA 690 on growth of urothelial HT-1376, J82, and RT-4 tumors xenografted into nude mice. The presence of GHRH receptors was validated by Western blotting. Results: The receptors for GHRH and their main splice variant, SV1, were detected in tumor samples of all 3 human bladder cancer models. In the HT-1376 tumors, the GHRH antagonists caused a 30-60% reduction in volume and 52-70% decrease in tumor weights (p < 0.05). All three antagonists strongly inhibited growth of J82 cancers as shown by a 62-75% reduction in tumor volume and 54-66% decrease in tumor weights (p < 0.05). Treatment with MIA-602 and MIA-606 resulted in a similar marked inhibition of growth of RT-4 cancers; tumor volume and weights were reduced by about 51-71% in the treated groups (p < 0.05). The mice tolerated this therapy well; body and organ weights were not significantly changed by the treatments. No toxicity from the GHRH antagonists was noted. Conclusions: We demonstrated the efficacy of potent GHRH antagonists and their lack of toxicity in inhibiting the growth of experimental models of bladder cancer in vivo. The expression of GHRH receptors was detected in all 3 models of human primary urothelial bladder carcinomas. Our findings warrant further development of GHRH antagonists for clinical therapy of bladder cancer alone or in combination with current chemotherapeutic agents and Exploration of their mechanism of action.

Suppression of the proliferation of human U-87 MG glioblastoma cells by new antagonists of growth hormone-releasing hormone in vivo and in vitro

2013 ◽  
Vol 8 (4) ◽  
pp. 281-290 ◽  
Author(s):  
Miklos Jaszberenyi ◽  
Andrew V. Schally ◽  
Norman L. Block ◽  
Marta Zarandi ◽  
Ren-Zhi Cai ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Releasing Hormone ◽  
Glioblastoma Cells ◽  
Releasing Hormone
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