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

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.

Download Full-text

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818865116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2226-2231 ◽

Cited By ~ 10

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.469 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 469-469 ◽

Cited By ~ 1

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.

Download Full-text

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

Cancers ◽

10.3390/cancers13163950 ◽

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.221 ◽

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.

Download Full-text