scholarly journals Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus.

1986 ◽  
Vol 78 (4) ◽  
pp. 906-913 ◽  
Author(s):  
L A Frohman ◽  
T R Downs ◽  
T C Williams ◽  
E P Heimer ◽  
Y C Pan ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Enzymatic Degradation ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone

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.

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

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 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.

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

Abstract 723: Agonist of Growth Hormone Releasing Hormone Enhances Angiogenic Therapy by Mesenchymal Stem Cells

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hong Yu ◽  
Qunchao Ma ◽  
Xiangyang Xia ◽  
Quanwei Tao ◽  
Kai Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Hormone ◽  
Mesenchymal Stem Cells ◽  
Nuclear Translocation ◽  
Full Potential ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Angiogenic Therapy

Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) represents a promising strategy for treating cardiovascular disease. However, the efficiency of such therapy is limited by poor cell survival and engraftment. Growth hormone-releasing hormone (GHRH) regulates growth and development through pleiotropic actions on multiple target cell and tissue types. Here we studied the effect of the GHRH agonist, JI-34, on MSC survival and angiogenic therapy in a mouse model of critical limb ischemia. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced endothelial tube formation in vitro. These effects were paralleled by increased phosphorylation and nuclear translocation of STAT3. In vivo, JI-34 pre-treatment enhanced the engraftment of MSCs into ischemic hindlimb muscles and augmented reperfusion and limb salvage compared with untreated MSCs. Significantly more vasculature and proliferating CD31+ and CD34+ cells were detected in ischemic muscles that received MSCs treated with JI-34. Our studies demonstrate a novel role for JI-34 to markedly improve therapeutic angiogenesis in hindlimb ischemia by increasing the viability and mobility of MSCs. These findings support additional studies to explore the full potential of GHRH agonists to augment cell therapy in the management of ischemia.

Theophylline blunts the GH-response to growth hormone releasing hormone in normal subjects

1986 ◽  
Vol 112 (4) ◽  
pp. 473-480 ◽  
Author(s):  
Marco Losa ◽  
Roland Huss ◽  
August König ◽  
O. Albrecht Müller ◽  
Klaus von Werder
Keyword(s):  
Growth Hormone ◽  
Normal Subjects ◽  
List Type ◽  
Growth Hormone Releasing Hormone ◽  
Test Procedures ◽  
Continuous Administration ◽  
Releasing Hormone ◽  
Gh Secretion

Abstract. Theophylline enhances GH-secretion in vitro, whereas in vivo a slight decrease of basal GH-levels has been observed. In the present study the effect of theophylline on the GH-responsiveness to acute and continuous administration of growth hormone releasing hormone (GHRH) was investigated. The following protocol was performed. GHRH study. Fifty μg GHRH was given as an iv bolus followed by constant GHRH-infusion (100 μg/h) over 2 h after which another GHRH bolus of 50 μg was given. GHRH plus theophylline study. GHRH was administered as in the first study and theophylline was infused at a constant rate of 3.56 mg/min over 3 h, starting one h before the GHRH bolus. Theophylline study. Only saline and theophylline were infused. GHRH alone led to a GH-rise within 30 min with a maximum of 22.8 ± 7.2 ng/ml (mean ± se) after which GH-levels decreased despite continuous GHRH-infusion to a nadir of 12.1 ± 4.4 ng/ml at 105 min. The second GHRH bolus led to a minimal GH-increase (13.3 ± 6.4 ng/ml at 135 min). Theophylline administration resulted in blunting of the GH-response to GHRH in all volunteers, with GH levels fluctuating between 4–6 ng/ml throughout GHRH-administration. Theophylline alone did not affect GH-levels in three subjects studied, whereas in the other one a GH secretory episode 90 min after administration of the drug was observed. Prl showed a minimal increase only after the second GHRH bolus (from 254.2 ± 7.7 μU/ml to 317.3 ± 96.0 μU/ml in study 1, and from 139.3 ± 26.9 μU/ml to 193.0 ± 32.6 μU/ml in study 2), TSH-levels did not change during any of the test-procedures and GHRH-levels were comparable in both study 1 and 2. Free fatty acids (FFA) rose progressively after theophylline administration (from 0.68 ± 0.10 mEq/l to 1.06 ± 0.08 mEq/l in study 2, and from 0.64 ± 0.12 mEq/l to 1.09 ± 0.05 mEq/l in study 3), but also after GHRH alone (from 0.50 ± 0.05 mEq/l to 0.78 ±0.11 mEq/l). This shows that therapeutical doses of theophylline blunt the GH-response to GHRH in normal subjects. The mechanisms involved may be a competition for the adenosine receptor at the pituitary, or an indirect effect mediated by the rise of FFA levels.

scholarly journals Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

2018 ◽  
Vol 115 (47) ◽  
pp. 12028-12033 ◽  
Author(s):  
Andrew V. Schally ◽  
Haibo Wang ◽  
Jinlin He ◽  
Renzhi Cai ◽  
Wei Sha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Hormone ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Growth Hormone Releasing Hormone ◽  
Down Regulation ◽  
Releasing Hormone ◽  
Inhibition Of Tumor Growth

The effects of the growth hormone-releasing hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27kip1, and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 μg/day for 4 to 8 weeks significantly suppressed growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex hormone-dependent cancers after the down-regulation of receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.

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