|
1
|
Pérez-Gómez JM, Montero-Hidalgo AJ, Luque RM. GHRH and reproductive systems: Mechanisms, functions, and clinical implications. Rev Endocr Metab Disord 2024:10.1007/s11154-024-09931-8. [PMID: 39612161 DOI: 10.1007/s11154-024-09931-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/05/2024] [Indexed: 11/30/2024]
Abstract
Growth hormone-releasing hormone (GHRH) has classically been considered a regulatory neuropeptide of the hypothalamic-pituitary system, which mediates its anabolic effects through hepatic GH/IGF-I axis. However, during the last decades it has been demonstrated that this key regulatory hormone may be produced in numerous peripheral tissues outside the central nervous system, participating in fundamental physiological functions through a complex balance between its purely endocrine action, and the recently local (autocrine/paracrine) discovered role. Among peripheral sites, its presence in the male and female reproductive systems stands out. In this review, we will first explore the role of the GHRH/GHRH-R hormone axis as a central player in the gonadal function; then, we will discuss available information regarding the presence of GHRH/GHRH-R and the potential physiological roles in reproductive systems of various species; and finally, we will address how reproductive system-related disorders-such as infertility problems, endometriosis, or tumor pathologies (including prostate, or ovarian cancer)-could benefit from hormonal interventions related to the manipulation of the GHRH axis.
Collapse
Affiliation(s)
- Jesús M Pérez-Gómez
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), IMIBIC Building. Av. Menéndez Pidal S/N. 14004, Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
| | - Antonio J Montero-Hidalgo
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), IMIBIC Building. Av. Menéndez Pidal S/N. 14004, Cordoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
| | - Raúl M Luque
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), IMIBIC Building. Av. Menéndez Pidal S/N. 14004, Cordoba, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de La Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.
| |
Collapse
|
|
2
|
Apoptotic Effects of Drug Targeting Conjugates Containing Different GnRH Analogs on Colon Carcinoma Cells. Int J Mol Sci 2019; 20:ijms20184421. [PMID: 31500399 PMCID: PMC6769516 DOI: 10.3390/ijms20184421] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 12/30/2022] Open
Abstract
The wide range of cellular target reactions (e.g., antitumor) of gonadotropin-releasing hormone (GnRH) variants provides the possibility to develop multifunctional GnRH conjugates. The aim of our work was to compare the cytotoxic/apoptotic activity of different GnRH-based, daunorubicin (Dau)-linked conjugates with or without butyrated Lys in position 4 (4Lys(Bu)) at a molecular level in a human colorectal carcinoma cell line. Cell viability was measured by impedimetry, cellular uptake and apoptosis were studied by flow cytometry, and the expression of apoptosis-related genes was analyzed by qRT-PCR. The modification with 4Lys(Bu) resulted in an increased cytotoxic and apoptotic effects and cellular uptake of the GnRH-I and GnRH-III conjugates. Depending on the GnRH isoform and the presence of 4Lys(Bu), the conjugates could regulate the expression of several apoptosis-related genes, especially tumor necrosis factor (TNF), tumor protein p53 (TP53) and the members of growth-factor signaling. The stronger cytotoxicity of GnRH-I and GnRH-III conjugates containing 4Lys(Bu) was associated with a stronger inhibitory effect on the expression of growth-factor signaling elements in comparison with their 4Ser counterparts, in which the upregulation of TP53 and caspases (e.g., CASP9) seemed to play a more important role. We were able to provide further evidence that targeting the GnRH receptor could serve as a successful therapeutic approach in colon cancer, and GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] proved to be the best candidate for this purpose.
Collapse
|
|
3
|
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma. Proc Natl Acad Sci U S A 2019; 116:2226-2231. [PMID: 30659154 PMCID: PMC6369772 DOI: 10.1073/pnas.1818865116] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis and limited treatment options. MPM remains a serious public health problem, and novel therapeutic strategies are urgently needed. The antitumor properties of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different cancers; however, their influence in MPM remains unexplored. Our work shows that GHRH antagonists MIA-602 and MIA-690 reduce survival, proliferation, and migration of human MPM cell lines and primary MPM cells in vitro by modulating apoptotic and oncogenic pathways. In vivo, GHRH antagonists inhibited the growth of MPM xenografts and blunted the production of growth factors in tumors. Overall, the inhibitory activities described in this study suggest that GHRH antagonists may be considered for development of therapies for MPM. 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.
Collapse
|
|
4
|
Ignacio DN, Mason KD, Hackett-Morton EC, Albanese C, Ringer L, Wagner WD, Wang PC, Carducci MA, Kachhap SK, Paller CJ, Mendonca J, Li-Ying Chan L, Lin B, Hartle DK, Green JE, Brown CA, Hudson TS. Muscadine grape skin extract inhibits prostate cancer cells by inducing cell-cycle arrest, and decreasing migration through heat shock protein 40. Heliyon 2019; 5:e01128. [PMID: 30705983 PMCID: PMC6348279 DOI: 10.1016/j.heliyon.2019.e01128] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/17/2018] [Accepted: 01/07/2019] [Indexed: 01/24/2023] Open
Abstract
Previously we demonstrated that muscadine grape skin extract (MSKE), a natural product, significantly inhibited androgen-responsive prostate cancer cell growth by inducing apoptosis through the targeting of survival pathways. However, the therapeutic effect of MSKE on more aggressive androgen-independent prostate cancer remains unknown. This study examined the effects of MSKE treatment in metastatic prostate cancer using complementary PC-3 cells and xenograft model. MSKE significantly inhibited PC-3 human prostate cancer cell tumor growth in vitro and in vivo. The growth-inhibitory effect of MSKE appeared to be through the induction of cell-cycle arrest. This induction was accompanied by a reduction in the protein expression of Hsp40 and cell-cycle regulation proteins, cyclin D1 and NF-kBp65. In addition, MSKE induced p21 expression independent of wild-type p53 induced protein expression. Moreover, we demonstrate that MSKE significantly inhibited cell migration in PC-3 prostate cancer cells. Overall, these results demonstrate that MSKE inhibits prostate tumor growth and migration, and induces cell-cycle arrest by targeting Hsp40 and proteins involved in cell-cycle regulation and proliferation. This suggests that MSKE may also be explored either as a neo-adjuvant or therapeutic for castration resistant prostate cancer.
Collapse
Affiliation(s)
- Diane N. Ignacio
- Howard University Cancer Center, Washington DC 20060, United States
- The University of the West Indies, St. Augustine Campus, Faculty of Medical Sciences, School of Pharmacy, Eric Williams Medical Sciences Complex, Champs Fleurs, Trinidad and Tobago
| | | | | | - Christopher Albanese
- Lombardi Cancer Center, Georgetown University Medical Center, Washington DC, United States
| | - Lymor Ringer
- Lombardi Cancer Center, Georgetown University Medical Center, Washington DC, United States
| | - William D. Wagner
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston Salem, NC 27157, United States
| | - Paul C. Wang
- Howard University Cancer Center, Washington DC 20060, United States
- College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Michael A. Carducci
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Sushant K. Kachhap
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Channing J. Paller
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Janet Mendonca
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Leo Li-Ying Chan
- Department of Technology R&D, Nexcelom Bioscience LLC, Lawrence, MA 01843, United States
| | - Bo Lin
- Department of Technology R&D, Nexcelom Bioscience LLC, Lawrence, MA 01843, United States
| | - Diane K. Hartle
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, United States
| | - Jeffrey E. Green
- Laboratory of Cell Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, United States
| | - Collis A. Brown
- Howard University Cancer Center, Washington DC 20060, United States
- Department of Pharmacology, Howard University College of Medicine, Washington DC 20059, United States
| | - Tamaro S. Hudson
- Howard University Cancer Center, Washington DC 20060, United States
- Department of Pharmacology, Howard University College of Medicine, Washington DC 20059, United States
- Department of Research, Washington VA Medical Center, Washington DC, United States
- Corresponding author.
| |
Collapse
|
|
5
|
Barabutis N, Schally AV, Siejka A. P53, GHRH, inflammation and cancer. EBioMedicine 2018; 37:557-562. [PMID: 30344124 PMCID: PMC6284454 DOI: 10.1016/j.ebiom.2018.10.034] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/10/2018] [Accepted: 10/10/2018] [Indexed: 12/26/2022] Open
Abstract
P53 is a transcription factor very often mutated in malignancies. It functions towards the regulation of important cellular activities, such as cell cycle, senescence and apoptosis. Since inflammation and cancer are strongly associated through common pathways, P53 can suppress inflammation in a plethora of human tissues. Growth Hormone - Releasing Hormone is a hypothalamic peptide with a great capacity to affect the complex networks of cellular regulation via GHRH - specific receptors. GHRH antagonistic and agonistic analogs have been developed for clinical applications, including treatment of benign prostatic hyperplasia, breast, prostate and lung cancers, diabetes and neurodegenerative diseases. The epicenter of the current manuscript is the protective role of P53 against inflammation and cancer and emphasizes the p53 – mediated beneficial effects of GHRH antagonists in various human diseases.
Inflammation is tightly associated with cancer. GHRH antagonists induce P53 expression. P53 exerts a protective effect against cancer and inflammation.
Collapse
Affiliation(s)
- Nektarios Barabutis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA.
| | - Andrew V Schally
- Department of Pathology and Divisions of Hematology/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33156, USA; Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33156, USA
| | - Agnieszka Siejka
- Department of Clinical Endocrinology, Medical University of Lodz, Poland
| |
Collapse
|
|
6
|
Faleiro M, Cintra L, Jesuino R, Damasceno A, Moura V. Expression of cell cycle inhibitors in canine prostate with proliferative inflammatory atrophy and carcinoma. ARQ BRAS MED VET ZOO 2018. [DOI: 10.1590/1678-4162-9472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
ABSTRACT Gene expression of CDKN1A, CDKN1B, and TP53, and immunostaining of p21, p27 and p53 were evaluated to verify the role of these cell cycle inhibitors in canine prostates with proliferative inflammatory atrophy-PIA and prostatic carcinoma-PC. Seventy samples, 15 normal, 30PIA and 25PC. Regarding number of p27 and p53 labeled cells, difference between normal and PIA and PC was observed, as well as between PIA and PC for p53. Immunostaining intensities of p21, p27 and p53 were different when comparing normal tissues to PIA and PC. Sixteen cDNA of canine prostatic FFPE tissue were subjected to RT-PCR and RT-qPCR, four normal, three PIA, and nine PC. CDKN1A mRNA was detected in four PC by RT-PCR, and it was overexpressed when compared to normal by RT-qPCR, in one PIA and six PC. CDKN1B mRNA was detected in three PC by RT-PCR and it was overexpressed in three PC and decreased in one PC. TP53 mRNA was overexpressed in one PIA and three PC. In conclusion, when overexpressed in canine prostate with premalignant and malignant, p21 and p27 play a role controlling cell proliferation, working as a protective factor in the evolution of PIA to PC, and in the PC development, even in the presence of altered p53.
Collapse
|
|
7
|
Muñoz-Moreno L, Bajo AM, Prieto JC, Carmena MJ. Growth hormone-releasing hormone (GHRH) promotes metastatic phenotypes through EGFR/HER2 transactivation in prostate cancer cells. Mol Cell Endocrinol 2017; 446:59-69. [PMID: 28193499 DOI: 10.1016/j.mce.2017.02.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 12/22/2022]
Abstract
The involvement of growth hormone-releasing hormone (GHRH) in several relevant processes that contribute to prostate cancer progression was analyzed. Firstly, we evaluated GHRH effects on cell proliferation and adhesion in human cancer prostate cell lines, LNCaP and PC3, by using specific assays (BrdU incorporation and collagen adhesion). The expression levels of the main marker molecules of these processes were measured by RT-PCR, Western blotting and zymography assays. GHRH increased both cell proliferation and proliferating cell nuclear antigen (PCNA) levels in LNCaP cells and in PC3 cells; however, such a rise was faster in the PC3 cells that represent the most aggressive stage of prostate cancer. Furthermore, GHRH significantly reduced cell adhesion and E-cadherin levels in LNCaP and PC3 cells and up-regulated the total and nuclear expression of β-catenin in PC3 cells. In addition, we assessed cell cycle, cell migration and VEGF secretion in PC3 cells. GHRH augmented the number of cells in G2/M-phase but diminished that corresponding to G1-phase. Cell-cycle specific markers were evaluated since GHRH effects may be related to their differential expression; we observed a decrease of p53, p21, and Bax/Bcl2 ratio. Furthermore, GHRH increased the expression of CD44, c-myc and cyclin D1, MMP-2 and MMP-9 activity, and VEGF secretion. We also observed that EGFR and/or HER2 transactivation is involved in cell adhesion, cell migration and VEGF secretion produced by GHRH. Consequently, present results define GHRH as a proliferative, anti-apoptotic and migratory agent in prostate cancer.
Collapse
Affiliation(s)
- Laura Muñoz-Moreno
- Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares 28871, Spain
| | - Ana M Bajo
- Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares 28871, Spain
| | - Juan C Prieto
- Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares 28871, Spain.
| | - María J Carmena
- Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares 28871, Spain
| |
Collapse
|
|
8
|
Zarandi M, Cai R, Kovacs M, Popovics P, Szalontay L, Cui T, Sha W, Jaszberenyi M, Varga J, Zhang X, Block NL, Rick FG, Halmos G, Schally AV. Synthesis and structure-activity studies on novel analogs of human growth hormone releasing hormone (GHRH) with enhanced inhibitory activities on tumor growth. Peptides 2017; 89:60-70. [PMID: 28130121 DOI: 10.1016/j.peptides.2017.01.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/10/2017] [Accepted: 01/23/2017] [Indexed: 12/21/2022]
Abstract
The syntheses and biological evaluations of new GHRH analogs of Miami (MIA) series with greatly increased anticancer activity are described. In the design and synthesis of these analogs, the following previous substitutions were conserved: D-Arg2, Har9, Abu15, and Nle27. Most new analogs had Ala at position 8. Since replacements of both Lys12 and Lys21 with Orn increased resistance against enzymatic degradation, these modifications were kept. The substitutions of Arg at both positions 11 and 20 by His were also conserved. We kept D-Arg28, Har29 -NH2 at the C-terminus or inserted Agm or 12-amino dodecanoic acid amide at position 30. We incorporated pentafluoro-Phe (Fpa5), instead of Cpa, at position 6 and Tyr(Me) at position 10 and ω-amino acids at N-terminus of some analogs. These GHRH analogs were prepared by solid-phase methodology and purified by HPLC. The evaluation of the activity of the analogs on GH release was carried out in vitro on rat pituitaries and in vivo in male rats. Receptor binding affinities were measured in vitro by the competitive binding analysis. The inhibitory activity of the analogs on tumor proliferation in vitro was tested in several human cancer cell lines such as HEC-1A endometrial adenocarcinoma, HCT-15 colorectal adenocarcinoma, and LNCaP prostatic carcinoma. For in vivo tests, various cell lines including PC-3 prostate cancer, HEC-1A endometrial adenocarcinoma, HT diffuse mixed β cell lymphoma, and ACHN renal cell carcinoma cell lines were xenografted into nude mice and treated subcutaneously with GHRH antagonists at doses of 1-5μg/day. Analogs MIA-602, MIA-604, MIA-610, and MIA-640 showed the highest binding affinities, 30, 58, 48, and 73 times higher respectively, than GHRH (1-29) NH2. Treatment of LNCaP and HCT-15 cells with 5μM MIA-602 or MIA-690 decreased proliferation by 40%-80%. In accord with previous tests in various human cancer lines, analog MIA-602 showed high inhibitory activity in vivo on growth of PC-3 prostate cancer, HT-mixed β cell lymphoma, HEC-1A endometrial adenocarcinoma and ACHN renal cell carcinoma. Thus, GHRH analogs of the Miami series powerfully suppress tumor growth, but have only a weak endocrine GH inhibitory activity. The suppression of tumor growth could be induced in part by the downregulation of GHRH receptors levels.
Collapse
Affiliation(s)
- Marta Zarandi
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Renzhi Cai
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Magdolna Kovacs
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Petra Popovics
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Luca Szalontay
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Tengjiao Cui
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Wei Sha
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Sylvester Comprehensive Cancer Center, Miami, FL, United States
| | - Miklos Jaszberenyi
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Jozsef Varga
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States
| | - XianYang Zhang
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Norman L Block
- South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Sylvester Comprehensive Cancer Center, Miami, FL, United States; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Ferenc G Rick
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Urology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, United States
| | - Gabor Halmos
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States
| | - Andrew V Schally
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; Sylvester Comprehensive Cancer Center, Miami, FL, United States.
| |
Collapse
|
|
9
|
Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells. Proc Natl Acad Sci U S A 2017; 114:1359-1364. [PMID: 28123062 DOI: 10.1073/pnas.1620884114] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH.
Collapse
|
|
10
|
Gan J, Ke X, Jiang J, Dong H, Yao Z, Lin Y, Lin W, Wu X, Yan S, Zhuang Y, Chu WK, Cai R, Zhang X, Cheung HS, Block NL, Pang CP, Schally AV, Zhang H. Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-κB signaling. Proc Natl Acad Sci U S A 2016; 113:14745-14750. [PMID: 27930339 PMCID: PMC5187693 DOI: 10.1073/pnas.1618582114] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.
Collapse
Affiliation(s)
- Jinfeng Gan
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Xiurong Ke
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Jiali Jiang
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Hongmei Dong
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Zhimeng Yao
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Yusheng Lin
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Wan Lin
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China
| | - Xiao Wu
- Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| | - Shumei Yan
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yixuan Zhuang
- Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| | - Wai Kit Chu
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Renzhi Cai
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125
- South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125
- Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Xianyang Zhang
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125
- South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125
- Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Herman S Cheung
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125
- South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL 33146
| | - Norman L Block
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Chi Pui Pang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou 515041, China
| | - Andrew V Schally
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125;
- South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125
- Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Hao Zhang
- Cancer Research Center, Shantou University Medical College, Shantou 515041, China;
- Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China
- Department of Biotherapy, Affiliated Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| |
Collapse
|
|
11
|
Schally AV, Perez R, Block NL, Rick FG. Potentiating effects of GHRH analogs on the response to chemotherapy. Cell Cycle 2015; 14:699-704. [PMID: 25648497 DOI: 10.1080/15384101.2015.1010893] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Growth hormone releasing hormone (GHRH) from hypothalamus nominatively stimulates growth hormone release from adenohypophysis. GHRH is also produced by cancers, acting as an autocrine/paracrine growth factor. This growth factor function is seen in lymphoma, melanoma, colorectal, liver, lung, breast, prostate, kidney, bladder cancers. Pituitary type GHRH receptors and their splice variants are also expressed in these malignancies. Synthetic antagonists of the GHRH receptor inhibit proliferation of cancers. Besides direct inhibitory effects on tumors, GHRH antagonists also enhance cytotoxic chemotherapy. GHRH antagonists potentiate docetaxel effects on growth of H460 non-small cell lung cancer (NSCLC) and MX-1 breast cancer plus suppressive action of doxorubicin on MX-1 and HCC1806 breast cancer. We investigated mechanisms of antagonists on tumor growth, inflammatory signaling, doxorubicin response, expression of drug resistance genes, and efflux pump function. Triple negative breast cancer cell xenografted into nude mice were treated with GHRH antagonist, doxorubicin, or their combination. The combination reduced tumor growth, inflammatory gene expression, drug-resistance gene expression, cancer stem-cell marker expression, and efflux-pump function. Thus, antagonists increased the efficacy of doxorubicin in HCC1806 and MX-1 tumors. Growth inhibition of H460 NSCLC by GHRH antagonists induced marked downregulation in expression of prosurvival proteins K-Ras, COX-2, and pAKT. In HT-29, HCT-116 and HCT-15 colorectal cancer lines, GHRH antagonist treatment caused cellular arrest in S-phase of cell cycle, potentiated inhibition of in vitro proliferation and in vivo growth produced by S-phase specific cytotoxic agents, 5-FU, irinotecan and cisplatin. This enhancement of cytotoxic therapy by GHRH antagonists should have clinical applications.
Collapse
Affiliation(s)
- Andrew V Schally
- a Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education ; Miami , FL USA
| | | | | | | |
Collapse
|
|
12
|
Schally AV, Block NL, Rick FG. New therapies for relapsed castration-resistant prostate cancer based on peptide analogs of hypothalamic hormones. Asian J Androl 2015; 17:925-8. [PMID: 26112478 PMCID: PMC4814950 DOI: 10.4103/1008-682x.152819] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
It is a pleasure to contribute our presentation at the International Prostate Forum of the Annual Meeting of the American Urological Association (AUA) to this special issue of the Asian Journal of Andrology.
Collapse
Affiliation(s)
- Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Medicine, Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Medicine, Division of Endocrinology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Norman L Block
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Medicine, Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125, USA
- Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33174, USA
| |
Collapse
|
|
13
|
Popovics P, Schally AV, Block NL, Rick FG. Preclinical therapy of benign prostatic hyperplasia with neuropeptide hormone antagonists. World J Clin Urol 2014; 3:184-194. [DOI: 10.5410/wjcu.v3.i3.184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/26/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α1-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels. However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition of autocrine insulin-like growth factors-I/II and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as suggesting a potential role for somatostatin analogs in experimental therapies.
Collapse
|
|
14
|
Antagonistic analogs of growth hormone-releasing hormone increase the efficacy of treatment of triple negative breast cancer in nude mice with doxorubicin; A preclinical study. Oncoscience 2014; 1:665-73. [PMID: 25593995 PMCID: PMC4278278 DOI: 10.18632/oncoscience.92] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 10/23/2014] [Indexed: 12/11/2022] Open
Abstract
Introduction This study evaluated the effects of an antagonistic analog of growth hormone-releasing hormone, MIA-602, on tumor growth, response to doxorubicin, expression of drug resistance genes, and efflux pump function in human triple negative breast cancers. Methods HCC1806 (doxorubicin-sensitive) and MX-1 (doxorubicin-resistant), cell lines were xenografted into nude mice and treated with MIA-602, doxorubicin, or their combination. Tumors were evaluated for changes in volume and the expression of the drug resistance genes MDR1 and NANOG. In-vitro cell culture assays were used to analyze the effect of MIA-602 on efflux pump function. Results Therapy with MIA-602 significantly reduced tumor growth and enhanced the efficacy of doxorubicin in both cell lines. Control HCC1806 tumors grew by 435%, while the volume of tumors treated with MIA-602 enlarged by 172.2% and with doxorubicin by 201.6%. Treatment with the combination of MIA-602 and doxorubicin resulted in an increase in volume of only 76.2%. Control MX-1 tumors grew by 907%, while tumors treated with MIA-602 enlarged by 434.8% and with doxorubicin by 815%. The combination of MIA-602 and doxorubicin reduced the increase in tumor volume to 256%. Treatment with MIA-602 lowered the level of growth hormone-releasing hormone and growth hormone-releasing hormone receptors and significantly reduced the expression of multidrug resistance (MDR1) gene and the drug resistance regulator NANOG. MIA-602 also suppressed efflux pump function in both cell lines. Conclusions We conclude that treatment of triple negative breast cancers with growth hormone-releasing hormone antagonists reduces tumor growth and potentiates the effects of cytotoxic therapy by nullifying drug resistance.
Collapse
|
|
15
|
Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer. Proc Natl Acad Sci U S A 2014; 111:1084-9. [PMID: 24395797 DOI: 10.1073/pnas.1323102111] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
Collapse
|
|
16
|
Szalontay L, Schally AV, Popovics P, Vidaurre I, Krishan A, Zarandi M, Cai RZ, Klukovits A, Block NL, Rick FG. Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function. Cell Cycle 2014; 13:2790-7. [PMID: 25486366 PMCID: PMC4615138 DOI: 10.4161/15384101.2015.945879] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/13/2014] [Accepted: 06/16/2014] [Indexed: 01/21/2023] Open
Abstract
Malignant melanoma is the deadliest form of skin cancer; the treatment of advanced and recurrent forms remains a challenge. It has recently been reported that growth hormone-releasing hormone (GHRH) receptor is involved in the pathogenesis of melanoma. Therefore, we investigated the effects of our new GHRH antagonists on a human melanoma cancer cell line. Antiproliferative effects of GHRH antagonists, MIA-602, MIA-606 and MIA-690, on the human melanoma cell line, A-375, were studied in vitro using the MTS assay. The effect of MIA-690 (5 μg/day 28 d) was further evaluated in vivo in nude mice bearing xenografts of A-375. Subcellular localization of p27 was detected with Western blot and immunofluorescent staining. MIA-690 inhibited the proliferation of A-375 cells in a dose-dependent manner (33% at 10 μM, and 19.2% at 5 μM, P < 0 .05 vs. control), and suppressed the growth of xenografted tumors by 70.45% (P < 0.05). Flow cytometric analysis of cell cycle effects following the administration of MIA-690 revealed a decrease in the number of cells in G2/M phase (from 19.7% to 12.9%, P < 0.001). Additionally, Western blot and immunofluorescent studies showed that exposure of A-375 cells to MIA-690 triggered the nuclear accumulation of p27. MIA-690 inhibited tumor growth in vitro and in vivo, and increased the translocation of p27 into the nucleus thus inhibiting progression of the cell cycle. Our findings indicate that patients with malignant melanoma could benefit from treatment regimens, which combine existing chemotherapy agents and novel GHRH-antagonists.
Collapse
Key Words
- ANOVA, one-way analysis of variance
- Abu, a-aminobutyric acid
- Ac, acetyl
- Ada, 12-aminododecanoyl
- Agm, agmatine
- Amc, 8-aminocaprylyl
- Cpa, parachlorophenylalanine
- FBS, fetal bovine serum
- Fpa5, pentafluoro-phenylalanine
- GH, growth hormone
- GHRH, growth hormone-releasing hormone
- GHRH-R, growth hormone-releasing hormone receptor
- Har, homoarginine
- IGF-I, insulin-like growth factor I
- MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfonphenyl)-2H-tetrazolium
- Nle, norleucine
- Orn, ornithine
- Ph, phenyl
- PhAc, phenylacetyl
- SVs, splice variants
- TBS, tris-buffered saline
- Tyr(Me), O-methyltyrosine
- growth hormone-releasing hormone antagonist
- hGHRH, human growth hormone-releasing hormone
- mTOR, mammalian target of rapamycin
- melanoma
- p27
- pGHRH-R, pituitary type GHRH-receptor
- targeted therapy
- xenografted mouse model
Collapse
Affiliation(s)
- Luca Szalontay
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
| | - Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
- Divisions of Hematology/Oncology; University of Miami; Miller School of Medicine; Miami, FL USA
- Department of Endocrinology; University of Miami; Miller School of Medicine; Miami, FL USA
- Sylvester Comprehensive Cancer Center; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Petra Popovics
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Cardiovascular Diseases; Department of Medicine; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Irving Vidaurre
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
| | - Awtar Krishan
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Marta Zarandi
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Ren-Zhi Cai
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Anna Klukovits
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Norman L Block
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Pathology; University of Miami; Miller School of Medicine; Miami, FL USA
- Divisions of Hematology/Oncology; University of Miami; Miller School of Medicine; Miami, FL USA
| | - Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education; Miami, FL USA
- Department of Urology; Herbert Wertheim College of Medicine; Florida International University; Miami, FL, USA
| |
Collapse
|
|
17
|
Rick FG, Block NL, Schally AV. Agonists of luteinizing hormone-releasing hormone in prostate cancer. Expert Opin Pharmacother 2013; 14:2237-47. [PMID: 23984804 DOI: 10.1517/14656566.2013.834328] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT. AREAS COVERED This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa. EXPERT OPINION The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging.
Collapse
Affiliation(s)
- Ferenc G Rick
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, South Florida Veterans Affairs Foundation for Research and Education , 1201 NW 16th St, Research (151), Room 2A103C, Miami, FL 33125 , USA +1 305 575 3477 ; +1 305 575 3126 ;
| | | | | |
Collapse
|
|
18
|
Jaszberenyi M, Rick FG, Szalontay L, Block NL, Zarandi M, Cai RZ, Schally AV. Beneficial effects of novel antagonists of GHRH in different models of Alzheimer's disease. Aging (Albany NY) 2013; 4:755-67. [PMID: 23211425 PMCID: PMC3560443 DOI: 10.18632/aging.100504] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease is the most frequent debilitating disorder of the central nervous system. Neuroendocrine mechanisms appear to play an important role in this insidiously developing disease. In the present study, the effects of a recently developed growth hormone-releasing hormone (GHRH) antagonist (MIA-690) were evaluated in vivo observing the behavior of genetically modified "Alzheimer's" 5XFAD mice in a Morris water maze (MWM). The effects of the antagonist were also evaluated in vitro using HCN2 human cortical cell cultures treated with amyloid-β1-42. In vivo, the indices of cognitive performance (latency, cumulative index etc.) were followed up for 6 months. In vitro, the formation of reactive oxygen species, markers of inflammatory and neurohormonal signaling were measured by fluorescent detection, PCR, and ELISA. Accumulation of amyloid-β1-42 rafts and τ filaments in necropsied brain samples was verified with the help of ELISA. In the MWM experiments, MIA-690 decreased escape latency, and, in the brain samples, it inhibited the concentration of amyloid-β1-42 and τ filaments. In cell cultures, the GHRH analog showed anti-oxidative and neuro-protective properties and inhibited the GHRH-growth hormone-insulin like growth factor axis. Our data strongly suggest the merit of further studies with GHRH analogs in models of Alzheimer's disease and in elementary clinical trials.
Collapse
Affiliation(s)
- Miklos Jaszberenyi
- Endocrine, Polypeptide, and Cancer Institute, Miami Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education, Miami, FL 33125, USA
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
PURPOSE OF REVIEW We provide new viewpoints of hormonal control of benign prostatic hyperplasia (BPH). The latest treatment findings with 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride, refined indications, efficacy, and safety are discussed and compared. We also discuss potential new 5-ARIs and other hormonal treatments. RECENT FINDINGS Finasteride and dutasteride have equal efficacy and safety for the treatment and prevention of progression of BPH. 5-ARIs are especially recommended for prostates greater than 40 ml and PSA greater than 1.5 ng/ml. Combination therapy is the treatment of choice in these patients, but with prostate volume greater than 58 ml or International Prostate Symptom Score of at least 20, combinations have no advantage over 5-ARI monotherapy. Updates on the recent developments on BPH therapy with luteinizing hormone-releasing hormone (LHRH) antagonist are also reviewed and analyzed. Preclinical studies suggest that growth hormone-releasing hormone (GHRH) antagonists effectively shrink experimentally enlarged prostates alone or in combination with LHRH antagonists. SUMMARY New 5-ARIs seem to be the promising agents that need further study. Preclinical studies revealed that GHRH and LHRH antagonists both can cause a reduction in prostate volume. Recent data indicate that prostate shrinkage is induced by the direct inhibitory action of GHRH and of LHRH antagonists exerted through prostatic receptors. The adverse effects of 5ARIs encourage alternative therapy.
Collapse
|
|
20
|
Rick FG, Block NL, Schally AV. An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer. Onco Targets Ther 2013; 6:391-402. [PMID: 23620672 PMCID: PMC3633549 DOI: 10.2147/ott.s32426] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Androgen deprivation therapy remains the mainstay of medical treatment for advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demonstrated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of advanced androgen-dependent prostate cancer.
Collapse
Affiliation(s)
- Ferenc G Rick
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | | | | |
Collapse
|
|
21
|
Sampson N, Neuwirt H, Puhr M, Klocker H, Eder IE. In vitro model systems to study androgen receptor signaling in prostate cancer. Endocr Relat Cancer 2013; 20:R49-64. [PMID: 23447570 DOI: 10.1530/erc-12-0401] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic.
Collapse
Affiliation(s)
- Natalie Sampson
- Division of Experimental Urology, Department of Urology, Innsbruck Medical University, Anichstraße 35, A-6020 Innsbruck, Austria
| | | | | | | | | |
Collapse
|
|
22
|
Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells. Mol Biol Rep 2012; 40:3925-33. [PMID: 23269627 DOI: 10.1007/s11033-012-2469-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
Abstract
We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774 cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.
Collapse
|
|
23
|
Rick FG, Seitz S, Schally AV, Szalontay L, Krishan A, Datz C, Stadlmayr A, Buchholz S, Block NL, Hohla F. GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer. Cell Cycle 2012; 11:4203-10. [PMID: 23095641 DOI: 10.4161/cc.22498] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G 1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40-55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56-85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.
Collapse
Affiliation(s)
- Ferenc G Rick
- Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Xu Y, Jiang Y, Wu B. New Agonist- and Antagonist-Based Treatment Approaches for Advanced Prostate Cancer. J Int Med Res 2012; 40:1217-26. [PMID: 22971474 DOI: 10.1177/147323001204000401] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based agonists and antagonists. In this review article, new therapy modalities and potential approaches for the treatment of advanced prostate cancer are discussed, including agonists and antagonists of luteinizing hormone-releasing hormone, antagonists of bombesin/gastrin-releasing peptide, and growth hormone-releasing hormone and somatostatin analogues. Though the prognosis of patients with prostate cancer is much improved by some of these treatment approaches, including combination treatment methods, extensive side-effects are still reported. These include sexual dysfunction, functional lesions of the liver and renal system, osteoporosis, anaemia and diarrhoea. Future studies should focus on new treatment agents and treatment approaches that can eliminate side-effects and improve quality of life in patients with prostate cancer on the basis of potent treatment efficacy.
Collapse
Affiliation(s)
- Y Xu
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yf Jiang
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
| | - B Wu
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
| |
Collapse
|
|
25
|
Muñoz-Moreno L, Arenas MI, Schally AV, Fernández-Martínez AB, Zarka E, González-Santander M, Carmena MJ, Vacas E, Prieto JC, Bajo AM. Inhibitory effects of antagonists of growth hormone-releasing hormone on growth and invasiveness of PC3 human prostate cancer. Int J Cancer 2012; 132:755-65. [PMID: 22777643 DOI: 10.1002/ijc.27716] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 06/11/2012] [Accepted: 06/22/2012] [Indexed: 01/28/2023]
Abstract
New approaches are needed to the therapy of advanced prostate cancer. This study determined the effect of growth hormone-releasing hormone (GHRH) antagonists, JMR-132 and JV-1-38 on growth of PC3 tumors as well as on angiogenesis and metastasis through the evaluation of various factors that contribute largely to the progression of prostate cancer. Human PC3 androgen-independent prostate cancer cells were injected subcutaneously into nude mice. The treatment with JMR-132 (10 μg/day) or JV-1-38 (20 μg/day) lasted 41 days. We also evaluated the effects of JMR-132 and JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of GHRH receptors and its splice variants, GHRH, vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF)-1α, metalloproteinases (MMPs) -2 and -9, β-catenin and E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3 tumors. After treatment with these analogues, we found an increase in expression of GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both VEGF and HIF-1α expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated β-catenin and a significant decline in E-cadherin. These results support that the blockade of GHRH receptors can modulate elements involved in angiogenesis and metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of androgen-independent prostate cancer.
Collapse
Affiliation(s)
- Laura Muñoz-Moreno
- Molecular Neuroendocrinology Unit, Department of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases. Proc Natl Acad Sci U S A 2012; 109:1655-60. [PMID: 22307626 DOI: 10.1073/pnas.1120588109] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors. We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tumors by 61% (P < 0.05). The expression of GHRH, GHRH receptors, and their main splice variant, SV1, in PC-3 cells and tumor xenografts was demonstrated by RT-PCR and Western blot. The content of GHRH protein in PC-3 xenografts was lowered markedly, by 66.3% (P < 0.01), after treatment with JMR-132. GHRH induced a significant increase in levels of ERK, but JMR-132 abolished this outcome. Our findings indicate that inhibition of PC-3 prostate cancer by JMR-132 involves inactivation of Akt and ERK. The inhibitory effect produced by GHRH antagonist can result in part from inactivation of the PI3K/Akt/mammalian target of rapamycin and Raf/MEK/ERK pathways and from the reduction in GHRH produced by cancer cells. Our findings support the role of GHRH as an autocrine growth factor in prostate cancer and suggest that antagonists of GHRH should be considered for further development as therapy for CRPC.
Collapse
|
|
27
|
Wang T, Hai J, Chen X, Peng H, Zhang H, Li L, Zhang Q. Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis. Endocr J 2012; 59:579-87. [PMID: 22572547 DOI: 10.1507/endocrj.ej11-0356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The aim of the current study is to investigate the effects of growth hormone releasing hormone (GHRH) antagonist on acetaminophen (APAP)-induced acute liver injury in mice. Healthy C57/B6L mice were orally treated with 200 mg/kg APAP with or without a 30-min pre-treatment with 300 µg/kg GHRH antagonist MZ-5-156. After 12 hours, serum, plasma, and liver samples from each mouse were collected for analyses. Our results showed that twelve-hour treatment with APAP caused obvious liver injury, elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increased oxidative stress, reduced expressions of antioxidant enzymes, accumulated expression of pro-inflammatory cytokines, and increased circulating levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I). Pre-treatment with MZ-5-156 aggravated liver injury, further increased serum ALT and AST levels, exacerbated oxidative stress and inflammation induced by APAP. Treatment of MZ-5-156 also blocked the phosphorylation form and total form of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Treatment of GHRH super-agonist JI-38 immediately after MZ-5-156 treatment partly reversed the liver injury caused by APAP and MZ-5-156. In conclusion, GHRH plays essential protective role in APAP-induced acute liver injury in vivo. The protective properties of GHRH are partially through GH/IGF-I axis and JAK/STAT pathway.
Collapse
Affiliation(s)
- Tao Wang
- First affiliated hospital, Xinxiang Medical University, Henan, China
| | | | | | | | | | | | | |
Collapse
|