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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.
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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.
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Costoya J, Gaumond SI, Chale RS, Schally AV, Jimenez JJ. A novel approach for the treatment of AML, through GHRH antagonism: MIA-602. Rev Endocr Metab Disord 2024:10.1007/s11154-024-09917-6. [PMID: 39417961 DOI: 10.1007/s11154-024-09917-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/07/2024] [Indexed: 10/19/2024]
Abstract
Acute myeloid leukemia (AML) is the most aggressive and prevalent form of leukemia in adults. The gold-standard intervention revolves around the use of chemotherapy, and in some cases hematopoietic stem cell transplantation. Drug resistance is a frequent complication resulting from treatment, as it stands there are limited clinical measures available for refractory AML besides palliative care. The goal of this review is to renew interest in a novel targeted hormone therapy in the treatment of AML utilizing growth hormone-releasing hormone (GHRH) antagonism, given it may provide a potential solution for current barriers to achieving complete remission post-therapy. Recapitulating pre-clinical evidence, GHRH antagonists (GHRH-Ant) have significant anti-cancer activity across experimental human AML cell lines in vitro and in vivo and demonstrate significant inhibition of cancer in drug resistant analogs of leukemic cell lines as well. GHRH-Ant act in manners that are orthogonal to anthracyclines and when administered in combination synergize to produce a more potent anti-neoplastic effect. Considering the adversities associated with standard AML therapies and the developing issue of drug resistance, MIA-602 represents a novel approach worth further investigation.
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Affiliation(s)
- Joel Costoya
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Simonetta I Gaumond
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Andrew V Schally
- Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
- Division of Hematology & Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
- Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joaquin J Jimenez
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
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Jeanne Dit Fouque K, Salgueiro LM, Cai R, Sha W, Schally AV, Fernandez-Lima F. Structural Motif Descriptors as a Way To Elucidate the Agonistic or Antagonistic Activity of Growth Hormone-Releasing Hormone Peptide Analogues. ACS OMEGA 2018; 3:7432-7440. [PMID: 31458901 PMCID: PMC6644384 DOI: 10.1021/acsomega.8b00375] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/21/2018] [Indexed: 05/05/2023]
Abstract
The synthesis of analogues of hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) is an efficient strategy for designing new therapeutic agents. Several promising synthetic agonist and antagonist analogues of GHRH have been developed based on amino acid mutations of the GHRH (1-29) sequence. Because structural information on the activity of the GHRH agonists or antagonists is limited, there is a need for more effective analytical workflows capable of correlating the peptide sequence with biological activity. In the present work, three GHRH agonists-MR-356, MR-406, and MR-409-and three GHRH antagonists-MIA-602, MIA-606, and MIA-690-were investigated to assess the role of substitutions in the amino acid sequence on structural motifs and receptor binding affinities. The use of high resolution trapped ion mobility spectrometry coupled to mass spectrometry allowed the observation of a large number of peptide-specific mobility bands (or structural motif descriptors) as a function of the amino acid sequence and the starting solution environment. A direct correlation was observed between the amino acid substitutions (i.e., basic residues and d/l-amino acids), the structural motif descriptors, and the biological function (i.e., receptor binding affinities of the GHRH agonists and antagonists). The simplicity, ease, and high throughput of the proposed workflow based on the structural motif descriptors can significantly reduce the cost and time during screening of new synthetic peptide analogues.
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Affiliation(s)
- Kevin Jeanne Dit Fouque
- Department
of Chemistry and Biochemistry, Florida International
University, 11200 SW 8th Street, AHC4-233, Miami, Florida 33199, United States
| | - Luis M. Salgueiro
- Veterans
Affairs Medical Center, 1201 NW 16th Street, Research Service (151), Room
2A103C, Miami, Florida 33125, United States
- Departments
of Pathology and Medicine, Divisions of Hematology/Oncology and Endocrinology,
Miller School of Medicine, University of
Miami, 1600 NW 10th Avenue
#1140, Miami, Florida 33136, United States
| | - Renzhi Cai
- Veterans
Affairs Medical Center, 1201 NW 16th Street, Research Service (151), Room
2A103C, Miami, Florida 33125, United States
- Departments
of Pathology and Medicine, Divisions of Hematology/Oncology and Endocrinology,
Miller School of Medicine, University of
Miami, 1600 NW 10th Avenue
#1140, Miami, Florida 33136, United States
| | - Wei Sha
- Veterans
Affairs Medical Center, 1201 NW 16th Street, Research Service (151), Room
2A103C, Miami, Florida 33125, United States
- Departments
of Pathology and Medicine, Divisions of Hematology/Oncology and Endocrinology,
Miller School of Medicine, University of
Miami, 1600 NW 10th Avenue
#1140, Miami, Florida 33136, United States
| | - Andrew V. Schally
- Veterans
Affairs Medical Center, 1201 NW 16th Street, Research Service (151), Room
2A103C, Miami, Florida 33125, United States
- Departments
of Pathology and Medicine, Divisions of Hematology/Oncology and Endocrinology,
Miller School of Medicine, University of
Miami, 1600 NW 10th Avenue
#1140, Miami, Florida 33136, United States
| | - Francisco Fernandez-Lima
- Department
of Chemistry and Biochemistry, Florida International
University, 11200 SW 8th Street, AHC4-233, Miami, Florida 33199, United States
- Biomolecular
Sciences Institute, Florida International
University, 11200 SW 8th Street, AHC4-211, Miami, Florida 33199, United States
- E-mail:
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NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [ 67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice. Molecules 2017; 22:molecules22111950. [PMID: 29137110 PMCID: PMC6150197 DOI: 10.3390/molecules22111950] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 11/06/2017] [Accepted: 11/08/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation.
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Maina T, Nock BA, Kulkarni H, Singh A, Baum RP. Theranostic Prospects of Gastrin-Releasing Peptide Receptor–Radioantagonists in Oncology. PET Clin 2017; 12:297-309. [PMID: 28576168 DOI: 10.1016/j.cpet.2017.02.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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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.
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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.
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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.
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Affiliation(s)
- Andrew V Schally
- a Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education ; Miami , FL USA
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Expression of Receptors for Pituitary-Type Growth Hormone-Releasing Hormone (pGHRH-R) in Human Papillary Thyroid Cancer Cells: Effects of GHRH Antagonists on Matrix Metalloproteinase-2. Discov Oncol 2015; 6:100-6. [DOI: 10.1007/s12672-015-0217-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/20/2015] [Indexed: 10/23/2022] Open
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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.
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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.
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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.
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Perez R, Schally AV, Vidaurre I, Rincon R, Block NL, Rick FG. Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers. Oncotarget 2013; 3:988-97. [PMID: 22941871 PMCID: PMC3660064 DOI: 10.18632/oncotarget.634] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFγ, IL-1α, IL-4, IL-6, IL-8, IL-10, and TNFα, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers.
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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.
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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.
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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
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Jaszberenyi M, Schally AV, Block NL, Zarandi M, Cai RZ, Vidaurre I, Szalontay L, Jayakumar AR, Rick FG. Suppression of the proliferation of human U-87 MG glioblastoma cells by new antagonists of growth hormone-releasing hormone in vivo and in vitro. Target Oncol 2013; 8:281-90. [PMID: 23371031 DOI: 10.1007/s11523-013-0264-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Accepted: 01/21/2013] [Indexed: 02/06/2023]
Abstract
Five-year survival of patients afflicted with glioblastoma multiforme (GBM) is rare, making this cancer one of the most feared malignancies. Previously, we reported that growth hormone-releasing hormone (GHRH) is a potent growth factor in cancers. The present work evaluated the effects of two antagonistic analogs of GHRH (MIA-604 and MIA-690) on the proliferation of U-87 MG GBM tumors, in vivo as well as in vitro. Both analogs were administered subcutaneously and dose-dependently inhibited the growth of tumors transplanted into nude mice (127 animals in seven groups). The analogs also inhibited cell proliferation in vitro, decreased cell size, and promoted apoptotic and autophagic processes. Both antagonists stimulated contact inhibition, as indicated by the expression of the E-cadherin-β-catenin complex and integrins, and decreased the release of humoral regulators of glial growth such as FGF, PDGFβ, and TGFβ, as revealed by genomic or proteomic detection methods. The GHRH analogs downregulated other tumor markers (Jun-proto-oncogene, mitogen-activated protein kinase-1, and melanoma cell adhesion molecule), upregulated tumor suppressors (p53, metastasis suppressor-1, nexin, TNF receptor 1A, BCL-2-associated agonist of cell death, and ifκBα), and inhibited the expression of the regulators of angiogenesis and invasion (angiopoetin-1, VEGF, matrix metallopeptidase-1, S100 calcium binding protein A4, and synuclein-γ). Our findings indicate that GHRH antagonists inhibit growth of GBMs by multiple mechanisms and decrease both tumor cell size and number.
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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.
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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
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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.
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Affiliation(s)
- Laura Muñoz-Moreno
- Molecular Neuroendocrinology Unit, Department of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain
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Stangelberger A, Schally AV, Rick FG, Varga JL, Baker B, Zarandi M, Halmos G. Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild-type p53 and decrease in p21 and mutant p53 proteins. Prostate 2012; 72:555-65. [PMID: 21796649 DOI: 10.1002/pros.21458] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 06/22/2011] [Indexed: 01/18/2023]
Abstract
BACKGROUND The tumor suppressor gene p53 is implicated in cell cycle control and apoptosis. Antagonists of growth hormone-releasing hormone (GHRH) have been shown to inhibit human experimental prostate cancers. METHODS We investigated the involvement of p53 apoptotic pathways in this effect. Nude mice bearing xenografted PC-3, DU-145, and MDA-PCa-2b human prostate cancer lines were treated with a new potent GHRH antagonist MZ-J-7-138. To determine whether tumor inhibition by MZ-J-7-138 involves apoptotic mechanisms such as p53 and p21, we evaluated by Western Blot the expression of mutant mt-p53 in PC-3 and DU-145 and of wild type (wt-p53) in MDA-PCa-2b prostate cancers as well as p21. RESULTS MZ-J-7-138 significantly inhibited the growth of PC-3, DU-145, and MDA-PCa-2b xenografts in nude mice. Androgen deprivation with the LHRH antagonist Cetrorelix enhanced the anti-proliferative effect of GHRH antagonist MZ-J-7-138 on MDA-PCa-2b tumors. The expression of mutant (mt-p53) and p21 protein in PC-3 and DU-145 tumors was significantly decreased by treatment with MZ-J-7-138, whereas wild type wt-p53 expression in MDA-PCA-2b tumors was up regulated by treatment with Cetrorelix. All three models investigated expressed specific, high affinity GHRH receptors. CONCLUSIONS Our findings indicate that the anti-proliferative effects of GHRH antagonist MZ-J-7-138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling.
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Rick FG, Szalontay L, Schally AV, Block NL, Nadji M, Szepeshazi K, Vidaurre I, Zarandi M, Kovacs M, Rekasi Z. Combining growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist greatly augments benign prostatic hyperplasia shrinkage. J Urol 2012; 187:1498-504. [PMID: 22341819 DOI: 10.1016/j.juro.2011.11.081] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Indexed: 12/20/2022]
Abstract
PURPOSE Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth hormone-releasing hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing hormone-releasing hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth hormone-releasing hormone and luteinizing hormone-releasing hormone on animal models of benign prostatic hyperplasia. MATERIALS AND METHODS We evaluated the effects of the growth hormone-releasing hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing hormone-releasing hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined biochemically and histologically. Serum levels of growth hormone, luteinizing hormone, insulin-like growth factor-1, dihydrotestosterone and prostate specific antigen were determined. RESULTS Marked shrinkage of the rat prostate (30.3%) occurred in response to the combination of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists (p<0.01). The combination strongly decreased prostatic prostate specific antigen, 6-transmembrane epithelial antigen of the prostate, interleukin-1β, nuclear factor-κβ and cyclooxygenase-2, and decreased serum prostate specific antigen. CONCLUSIONS A combination of growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist potentiated a reduction in prostate weight in an experimental benign prostatic hyperplasia model. Results suggest that this shrinkage in prostate volume was induced by the direct inhibitory effects of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists exerted through their respective prostatic receptors. These findings suggest that growth hormone-releasing hormone antagonists and/or their combination with luteinizing hormone-releasing hormone antagonists should be considered for further development as therapy for benign prostatic hyperplasia.
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Affiliation(s)
- Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida 33125, USA.
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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.
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Klukovits A, Schally AV, Szalontay L, Vidaurre I, Papadia A, Zarandi M, Varga JL, Block NL, Halmos G. Novel antagonists of growth hormone-releasing hormone inhibit growth and vascularization of human experimental ovarian cancers. Cancer 2011; 118:670-80. [PMID: 21751186 DOI: 10.1002/cncr.26291] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 04/08/2011] [Accepted: 04/25/2011] [Indexed: 11/11/2022]
Abstract
BACKGROUND Antagonists of growth hormone-releasing hormone (GHRH) inhibit the proliferation of various human cancer cell lines and experimental tumors by mechanisms that include direct action on GHRH receptors in cancer cells. METHODS In this study, the effects of newly synthesized GHRH antagonists, MIA-313, MIA-602, MIA-604, and MIA-610, were investigated in 2 human ovarian epithelial adenocarcinoma cell lines, OVCAR-3 and SKOV-3, in vitro and in vivo. The expression of receptors for GHRH was demonstrated by Western blot analysis and ligand competition methods in the OVCAR-3 and SKOV-3 cell lines and in tumors from those cells grown in athymic nude mice. The effects of GHRH antagonists on the secretion of vascular endothelial growth factor (VEGF) by OVCAR-3 cells and on the vascularization of OVCAR-3 xenografts also were evaluated. RESULTS Both the pituitary and the splice variant type 1 (SV1) GHRH receptors were detected in the 2 cell lines and in tumor xenografts, and SV1 was expressed at higher levels. Cell viability assays revealed the antiproliferative effect of all GHRH antagonists that were. Maximal tumor growth inhibition was approximately 75% in both models. MIA-313 and MIA-602 decreased VEGF secretion of OVCAR-3 cells, as measured by enzyme-linked immunosorbent assay, and reduced tumor vascularization in a Matrigel plug assay, but caused no change in the expression of VEGF or VEGF receptor in the terminal ileum of mice with OVCAR-3 tumors. CONCLUSIONS Results from the current study indicated that a he novel approach based on GHRH antagonists may offer more effective therapeutic alternatives for patients with advanced ovarian cancer and who do not tolerate conventional anti-VEGF therapy.
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Affiliation(s)
- Anna Klukovits
- Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida, USA
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Rick FG, Schally AV, Block NL, Halmos G, Perez R, Fernandez JB, Vidaurre I, Szalontay L. LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate 2011; 71:736-47. [PMID: 20945403 DOI: 10.1002/pros.21289] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Accepted: 09/07/2010] [Indexed: 01/20/2023]
Abstract
BACKGROUND Recent findings suggest that BPH has an inflammatory component. Clinical trials have documented that therapy with LHRH antagonist Cetrorelix causes a marked and prolonged improvement in LUTS in men with symptomatic BPH. We investigated the mechanism of action and effect of Cetrorelix in a rat model of BPH. METHODS Adult male Wistar rats were used. BPH was induced in rats by subcutaneous injections of TE 2 mg/day for 4 weeks. Control animals received injections of corn oil. After induction of BPH, rats received depot Cetrorelix pamoate at the doses of 0.625, 1.25, and 12.5 mg/kg on days 1 and 22 and TE-control rats received vehicle injections. Whole prostates were weighed and processed for RNA and protein. Real-time RT-PCR assays for numerous inflammatory cytokines and growth factors were performed. Quantitative analyses of prostatic LHRH receptor, LHRH, androgen receptor (AR) and 5α-reductase 2 were done by real-time RT-PCR and immunoblotting; serum DHT, LH, PSA, and IGF-1 by immunoassays. RESULTS mRNA levels for inflammatory cytokines IFN-γ, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-15, and IL-17 and for growth factors EGF, FGF-2, FGF-7, FGF-8, FGF-14, TGF-β1, and VEGF-A were significantly reduced by Cetrorelix 0.625 mg/kg (P < 0.05). Prostate weights were also significantly lowered by any dose of Cetrorelix. CONCLUSIONS This study suggests that Cetrorelix reduces various inflammatory cytokines and growth factors in rat prostate and, at doses which do not induce castration levels of testosterone, can lower prostate weights. Our findings shed light on the mechanism of action of LHRH antagonists in BPH.
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Affiliation(s)
- Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida 33125, USA
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Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. Proc Natl Acad Sci U S A 2011; 108:3755-60. [PMID: 21321192 DOI: 10.1073/pnas.1018086108] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Growth hormone-releasing hormone (GHRH), a hypothalamic polypeptide, acts as a potent autocrine/paracrine growth factor in many cancers. Benign prostatic hyperplasia (BPH) is a pathologic proliferation of prostatic glandular and stromal tissues; a variety of growth factors and inflammatory processes are inculpated in its pathogenesis. Previously we showed that potent synthetic antagonists of GHRH strongly inhibit the growth of diverse experimental human tumors including prostate cancer by suppressing various tumoral growth factors. The influence of GHRH antagonists on animal models of BPH has not been investigated. We evaluated the effects of the GHRH antagonists JMR-132 given at doses of 40 μg/d, MIA-313 at 20 μg/d, and MIA-459 at 20 μg/d in testosterone-induced BPH in Wistar rats. Reduction of prostate weights was observed after 6 wk of treatment with GHRH antagonists: a 17.8% decrease with JMR-132 treatment; a 17.0% decline with MIA-313 treatment; and a 21.4% reduction with MIA-459 treatment (P < 0.05 for all). We quantified transcript levels of genes related to growth factors, inflammatory cytokines, and signal transduction and identified significant changes in the expression of more than 80 genes (P < 0.05). Significant reductions in protein levels of IL-1β, NF-κβ/p65, and cyclooxygenase-2 (COX-2) also were observed after treatment with a GHRH antagonist. We conclude that GHRH antagonists can lower prostate weight in experimental BPH. This reduction is caused by the direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors. This study sheds light on the mechanism of action of GHRH antagonists in BPH and suggests that GHRH antagonists should be considered for further development as therapy for BPH.
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Kovács M, Schally AV, Hohla F, Rick FG, Pozsgai E, Szalontay L, Varga JL, Zarándi M. A correlation of endocrine and anticancer effects of some antagonists of GHRH. Peptides 2010; 31:1839-46. [PMID: 20633588 DOI: 10.1016/j.peptides.2010.07.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 07/05/2010] [Accepted: 07/05/2010] [Indexed: 01/22/2023]
Abstract
GHRH receptor antagonists inhibit growth and metastasis of a large number of experimental tumors expressing the pituitary GHRH receptor (pGHRH-R) and its major splice variant SV1. In this study, using Western blot, we demonstrated that DBTRG-05 and U-87MG human glioblastoma cell lines express pGHRH-R at levels 6-15 times higher than SV1. To reveal a correlation between the anticancer activity and the endocrine potency on inhibition of GH release, we compared the antitumor effect of GHRH antagonists JV-1-63 and MZJ-7-138 on growth of DBTRG-05 human glioblastomas grafted into athymic nude mice with their inhibitory potency on GH release. JV-1-63 strongly suppressed the stimulated GH secretion induced by clonidine in rats and inhibited the exogenous GHRH-induced GH surge by 88-99% in vivo and in vitro. MZJ-7-138 decreased the stimulated GH secretion by 58% in vitro and showed only a tendency to inhibit GH secretion in vivo. The strong inhibitor of GH release JV-1-63 reduced tumor growth of DBTRG-05 glioblastomas in nude mice by 46%, while the weak GH release suppressor MZJ-7-138 did not have an effect. Exposure of DBTRG-05 cells to the GHRH antagonists in vitro caused an upregulation of mRNA expression for pGHRH-R and a downregulation of SV1 expression, with JV-1-63 having significantly greater effects than MZJ-7-138. Our results demonstrate that a positive correlation exists between the endocrine potency and the antiproliferative efficacy of GHRH antagonists in tumors strongly expressing pGHRH-R.
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Affiliation(s)
- Magdolna Kovács
- Department of Anatomy, University of Pécs, Medical School, 7624 Pécs, Hungary.
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Stepień T, Sacewicz M, Lawnicka H, Krupiński R, Komorowski J, Siejka A, Stepień H. Stimulatory effect of growth hormone-releasing hormone (GHRH(1-29)NH2) on the proliferation, VEGF and chromogranin A secretion by human neuroendocrine tumor cell line NCI-H727 in vitro. Neuropeptides 2009; 43:397-400. [PMID: 19747727 DOI: 10.1016/j.npep.2009.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2009] [Revised: 07/14/2009] [Accepted: 08/14/2009] [Indexed: 11/23/2022]
Abstract
Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in a variety of cellular processes like cell survival, proliferation, apoptosis, angiogenesis and neoplastic transformation of various non-pituitary tissues. Here, we investigated for the first time the in vitro effect of GHRH(1-29)NH2 on the proliferation and the secretion of vascular endothelial growth factor (VEGF) and chromogranin A by the human bronchial neuroendocrine tumor cells NCI-H727. GHRH(1-29)NH2 at the concentrations of 10(-8)-10(-6)M increased the proliferation of these cells and this effect was associated with a statistically significant increase in VEGF and chromogranin A secretion into the supernatants of the tested cells. Our findings indicate that GHRH functions as a trophic hormone for bronchial neuroendocrine (NET) tumors.
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Affiliation(s)
- Tomasz Stepień
- Department of General and Endocrinological Surgery, Copernicus Memorial Hospital, Pabianicka Street 62, 93-513 Lodz, Poland
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Simmons MN, Klein EA. Combined Androgen Blockade Revisited: Emerging Options for the Treatment of Castration-Resistant Prostate Cancer. Urology 2009; 73:697-705. [PMID: 19185908 DOI: 10.1016/j.urology.2008.09.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 09/11/2008] [Accepted: 09/16/2008] [Indexed: 01/05/2023]
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