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Grujić M, Živković Radojević M, Janković K, Milosavljević N. Andrew Victor Schally: Pioneering Neuroendocrinologist and Architect of Luteinizing Hormone-Releasing Hormone Analogs. Cureus 2024; 16:e69137. [PMID: 39398731 PMCID: PMC11467473 DOI: 10.7759/cureus.69137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
Andrew Victor Schally is a pioneering figure in endocrinology and neuroendocrinology, whose work has fundamentally transformed the understanding and treatment of hormone-related disorders and cancer. His research, particularly in the isolation, characterization, and clinical application of hypothalamic hormones, has been instrumental in advancing medical science. Schally's early life, marked by the adversities of World War II, shaped his resilience and determination, driving him to pursue a career in medical research. His groundbreaking discovery of luteinizing hormone-releasing hormone (LHRH) and its analogs revolutionized the treatment of hormone-dependent cancers, especially advanced prostate cancer, by providing an effective alternative to surgical castration. Beyond LHRH, Schally's contributions to the development of somatostatin analogs have also had a significant impact on the management of acromegaly and neuroendocrine tumors. This article reviews Schally's life and work, emphasizing his contributions to endocrinology, particularly in the context of LHRH and its clinical applications. The review outlines his early life and education, his pioneering research on hypothalamic hormones, and the development of LHRH analogs that have become a cornerstone in the treatment of prostate cancer. Schally's ability to translate basic scientific discoveries into practical therapeutic strategies has earned him numerous accolades, including the Nobel Prize in Physiology or Medicine in 1977. His legacy continues to inspire and guide research in endocrinology and oncology, underscoring the lasting impact of his scientific achievements.
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Affiliation(s)
- Miloš Grujić
- Clinical Oncology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac, SRB
| | | | - Katarina Janković
- Clinical Oncology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac, SRB
| | - Neda Milosavljević
- Clinical Oncology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac, SRB
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Wang J, Zhang X, Xing J, Gao L, Lu H. Nanomedicines in diagnosis and treatment of prostate cancers: an updated review. Front Bioeng Biotechnol 2024; 12:1444201. [PMID: 39318666 PMCID: PMC11420853 DOI: 10.3389/fbioe.2024.1444201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 08/05/2024] [Indexed: 09/26/2024] Open
Abstract
Prostate cancer (PC) is the third most common male cancer in the world, which occurs due to various mutations leading to the loss of chromatin structure. There are multiple treatments for this type of cancer, of which chemotherapy is one of the most important. Sometimes, a combination of different treatments, such as chemotherapy, radiotherapy, and surgery, are used to prevent tumor recurrence. Among other treatments, androgen deprivation therapy (ADT) can be mentioned, which has had promising results. One of the drawbacks of chemotherapy and ADT treatments is that they are not targeted to the tumor tissue. For this reason, their use can cause extensive side effects. Treatments based on nanomaterials, known as nanomedicine, have attracted much attention today. Nanoparticles (NPs) are one of the main branches of nanomedicine, and they can be made of different materials such as polymer, metal, and carbon, each of which has distinct characteristics. In addition to NPs, nanovesicles (NVs) also have therapeutic applications in PC. In treating PC, synthetic NVs (liposomes, micelles, and nanobubbles) or produced from cells (exosomes) can be used. In addition to the role that NPs and NVs have in treating PC, due to being targeted, they can be used to diagnose PC and check the treatment process. Knowing the characteristics of nanomedicine-based treatments can help design new treatments and improve researchers' understanding of tumor biology and its rapid diagnosis. In this study, we will discuss conventional and nanomedicine-based treatments. The results of these studies show that the use of NPs and NVs in combination with conventional treatments has higher efficacy in tumor treatment than the individual use of each of them.
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Affiliation(s)
- Jiajia Wang
- Department of Oncology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
| | - Xuan Zhang
- Department of Urology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
| | - Jiazhen Xing
- Department of Urology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
| | - Lijian Gao
- Department of Urology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
| | - Hua Lu
- Department of Urology, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
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van Winden LJ, Lanfermeijer M, Heijboer AC, van Tellingen O, Bergman AM, van der Poel HG, Jonker N, van Rossum HH. Retrospective analysis of serum testosterone levels by LC-MS/MS in chemically castrated prostate cancer patients: Biological variation and analytical performance specifications. Clin Chim Acta 2021; 521:70-75. [PMID: 34217697 DOI: 10.1016/j.cca.2021.06.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND A sensitive liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was used to monitor serum testosterone levels in castrated prostate cancer patients. We subsequently performed an observational and retrospective study to estimate the within- and between-subject biological variation of these patients. METHODS In total, 474 samples from 72 prostate cancer patients in the Netherlands receiving either chemical castration (CAS) or castration plus enzalutamide (ENZA) treatment were selected for data analysis. ANOVA was performed to estimate analytical variation (CVA) and within-patient variation (CVI). A nested ANOVA was applied to estimate between-patient variation (CVG). From these data, the reference change value (RCV) and analytical performance specifications (APS) were calculated. RESULTS Testosterone levels were significantly higher in the ENZA group (0.318 vs. 0.191 nmol/L, p < 0.005) than the CAS group. Overall, variation components were estimated at 6.1%, 24.6% and 60.3% for CVA, CVI and CVG, respectively. Both groups showed high individuality (<0.6). The RCV was 70.3% for all patients. Desirable APS were 12.3% for imprecision, 16.3% for bias and 26.4% for total error. CONCLUSION The generated APS are valuable for sensitive testosterone assays and the high individuality indicates that castrated testosterone levels can be studied as a predictive or prognostic biomarker in prostate cancer patients.
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Affiliation(s)
- Lennart J van Winden
- Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Mirthe Lanfermeijer
- Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Annemieke C Heijboer
- Department of Clinical Chemistry: Laboratory for Endocrinology, Amsterdam University Medical Center, Location Amsterdam Medical Center and Location Free University of Amsterdam, Amsterdam, the Netherlands
| | - Olaf van Tellingen
- Department of Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Andries M Bergman
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Henk G van der Poel
- Department of Urology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Niels Jonker
- Certe, Wilhelmina Ziekenhuis Assen, Assen, the Netherlands
| | - Huub H van Rossum
- Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands
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Liu YF, Fu SQ, Yan YC, Gong BB, Xie WJ, Yang XR, Sun T, Ma M. Progress in Clinical Research on Gonadotropin-Releasing Hormone Receptor Antagonists for the Treatment of Prostate Cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:639-649. [PMID: 33623372 PMCID: PMC7896730 DOI: 10.2147/dddt.s291369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/20/2021] [Indexed: 01/04/2023]
Abstract
Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.
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Affiliation(s)
- Yi-Fu Liu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Sheng-Qiang Fu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Yu-Chang Yan
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Bin-Bin Gong
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Wen-Jie Xie
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Xiao-Rong Yang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Ting Sun
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
| | - Ming Ma
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People's Republic of China
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Tzoupis H, Nteli A, Androutsou ME, Tselios T. Gonadotropin-Releasing Hormone and GnRH Receptor: Structure, Function and Drug Development. Curr Med Chem 2021; 27:6136-6158. [PMID: 31309882 DOI: 10.2174/0929867326666190712165444] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Gonadotropin-Releasing Hormone (GnRH) is a key element in sexual maturation and regulation of the reproductive cycle in the human organism. GnRH interacts with the pituitary cells through the activation of the Gonadotropin Releasing Hormone Receptors (GnRHR). Any impairments/dysfunctions of the GnRH-GnRHR complex lead to the development of various cancer types and disorders. Furthermore, the identification of GnRHR as a potential drug target has led to the development of agonist and antagonist molecules implemented in various treatment protocols. The development of these drugs was based on the information derived from the functional studies of GnRH and GnRHR. OBJECTIVE This review aims at shedding light on the versatile function of GnRH and GnRH receptor and offers an apprehensive summary regarding the development of different agonists, antagonists and non-peptide GnRH analogues. CONCLUSION The information derived from these studies can enhance our understanding of the GnRH-GnRHR versatile nature and offer valuable insight into the design of new more potent molecules.
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Affiliation(s)
| | - Agathi Nteli
- Department of Chemistry, University of Patras, Rion GR-26504, Greece
| | - Maria-Eleni Androutsou
- Vianex S.A., Tatoiou Str., 18th km Athens-Lamia National Road, Nea Erythrea 14671, Greece
| | - Theodore Tselios
- Department of Chemistry, University of Patras, Rion GR-26504, Greece
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Singla N, Ghandour RA, Raj GV. Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer. Expert Opin Investig Drugs 2019; 28:249-259. [PMID: 30649971 DOI: 10.1080/13543784.2019.1570130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials. AREAS COVERED We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility. EXPERT OPINION Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.
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Affiliation(s)
- Nirmish Singla
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Rashed A Ghandour
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Ganesh V Raj
- a Department of Urology , University of Texas Southwestern Medical Center , Dallas , TX , USA
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Synthesis, Stability and Direct Antiproliferative Effect of New Cysteine Modified GnRH Analogs. Int J Pept Res Ther 2018. [DOI: 10.1007/s10989-018-9781-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Morote J, Comas I, Ferrer R, Planas J, Celma A, Regis L. Accuracy of serum luteinizing hormone and serum testosterone measurements to assess the efficacy of medical castration in prostate cancer patients. J Biomed Sci 2017; 24:81. [PMID: 29058606 PMCID: PMC5651562 DOI: 10.1186/s12929-017-0386-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/07/2017] [Indexed: 01/28/2023] Open
Abstract
Background Luteinizing hormone-releasing hormone (LH-RH) agonists are the standard for androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. Current guidelines recommend serum testosterone measurement to assess the efficacy of ADT and to define castration resistance. However, serum testosterone does not reflect the exclusive effect of castration due to its extratesticular production. The aim of this study is to analyze if serum LH reflects better than serum testosterone the activity of LH-RH agonists. Methods Serum LH and serum testosterone were measured with chemiluminescent immunoassay (CLIA) in a cohort study of 1091 participants: 488 PCa patients “on LH-RH agonists”, 303 “off LH-RH agonist” in whom LH-RH agonists were withdrawn, and 350 men with PCa suspicion “no LH-RH agonist” who never received LH-RH agonists. In a validation cohort of 147 PCa patients, 124 on “LH-RH agonists” and 19 “off LH-RH agonists”, serum testosterone was also measured with liquid chromatography and tandem mass spectrometry (LC MSMS). Results The area under the curve (AUC) to distinguish patients “on versus off LH-RH agonists” was 0.997 for serum LH and 0.740 for serum testosterone, P < 0.001. The 97.5 percentile of serum LH in patients “on LH-RH agonists” was 0.97 U/L, been the most efficient threshold 1.1 U/L. The AUCs for serum LH, testosterone measured with CLIA and with LC MSMS, in the validation cohort, were respectively 1.000, 0.646 and 0.814, P < 0.001. The efficacy to distinguish patients “on versus off LH-RH agonists” was 98.6%, 78.3%, and 89.5% respectively, using 1.1 U/L as threshold for serum LH and 50 ng/dL for serum testosterone regardless the method. Conclusions Serum LH is more accurate than serum testosterone regardless the method, to distinguish patients “on versus off LH-RH agonists”. The castrate level of serum LH is 1.1 U/l. These findings suggest that assessment of LH-RH agonist efficacy and castration resistance definition should be reviewed.
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Affiliation(s)
- Juan Morote
- Department of Urology, Vall d'Hebron Hospital, Universidad Autonoma de Barcelona, 14 Po Vall d'Hebron 119-129, 00173, Barcelona, Spain.
| | - Imma Comas
- Department of Biochemistry, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Roser Ferrer
- Department of Biochemistry, Vall d'Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jacques Planas
- Department of Urology, Vall d'Hebron Hospital, Universidad Autonoma de Barcelona, 14 Po Vall d'Hebron 119-129, 00173, Barcelona, Spain
| | - Anna Celma
- Department of Urology, Vall d'Hebron Hospital, Universidad Autonoma de Barcelona, 14 Po Vall d'Hebron 119-129, 00173, Barcelona, Spain
| | - Lucas Regis
- Department of Urology, Vall d'Hebron Hospital, Universidad Autonoma de Barcelona, 14 Po Vall d'Hebron 119-129, 00173, Barcelona, Spain
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9
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Henninot A, Collins JC, Nuss JM. The Current State of Peptide Drug Discovery: Back to the Future? J Med Chem 2017; 61:1382-1414. [PMID: 28737935 DOI: 10.1021/acs.jmedchem.7b00318] [Citation(s) in RCA: 689] [Impact Index Per Article: 86.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this Perspective, we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been critical to the discovery, design, and subsequent development of novel therapeutics.
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Affiliation(s)
- Antoine Henninot
- Ferring Research Institute , 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States
| | - James C Collins
- Ferring Research Institute , 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States
| | - John M Nuss
- Ferring Research Institute , 4245 Sorrento Valley Boulevard, San Diego, California 92121, United States
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Schally AV, Block NL, Rick FG. Discovery of LHRH and development of LHRH analogs for prostate cancer treatment. Prostate 2017; 77:1036-1054. [PMID: 28449236 DOI: 10.1002/pros.23360] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 01/06/2023]
Abstract
The discovery, isolation, elucidation of structure, synthesis, and initial testing of the neuropeptide hypothalamic luteinizing hormone-releasing hormone (LHRH), which regulates reproduction, is briefly described. The design, synthesis, and experimental and clinical testing of agonistic analogs of LHRH is extensively reviewed focusing on the development of new methods for the treatment of prostate cancer. Subsequent development of antagonistic analogs of LHRH is then faithfully recounted with special emphasis on therapy of prostate cancer and BPH. The concepts of targeted therapy to peptide receptors on tumors are re-examined and the development of the cytotoxic analogs of LHRH and their status is reviewed. The endeavor to develop better therapies for prostate cancer, based on LHRH analogs, guided much of our work.
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Affiliation(s)
- Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida
- Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Norman L Block
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida
- Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida
- Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida
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Lappano R, Maggiolini M. Pharmacotherapeutic Targeting of G Protein-Coupled Receptors in Oncology: Examples of Approved Therapies and Emerging Concepts. Drugs 2017; 77:951-965. [PMID: 28401445 DOI: 10.1007/s40265-017-0738-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
G protein-coupled receptors (GPCRs) are involved in numerous physio-pathological processes, including the stimulation of cancer progression. In this regard, it should be mentioned that although GPCRs may represent major pharmaceutical targets, only a few drugs acting as GPCR inhibitors are currently used in anti-tumor therapies. For instance, certain pro-malignancy effects mediated by GPCRs are actually counteracted by the use of small molecules and peptides that function as receptor antagonists or inverse agonists. Recently, humanized monoclonal antibodies targeting GPCRs have also been developed. Here, we review the current GPCR-targeted therapies for cancer treatment, summarizing the clinical studies that led to their official approval. We provide a broad overview of the mechanisms of action of the available anti-cancer drugs targeting gonadotropin-releasing hormone, somatostatin, chemokine, and Smoothened receptors. In addition, we discuss the anti-tumor potential of novel non-approved molecules and antibodies able to target some of the aforementioned GPCRs in different experimental models and clinical trials. Likewise, we focus on the repurposing in cancer patients of non-oncological GPCR-based drugs, elucidating the rationale behind this approach and providing clinical evidence on their safety and efficacy.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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Balaev AN, Okhmanovich KA, Fedorov VE. Convenient Four-Step Synthesis of H-Pyr-His-Trp-OH, a Key Tripeptide Intermediate for the Production of Synthetic Gonadoliberin Agonists. Pharm Chem J 2016. [DOI: 10.1007/s11094-016-1421-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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13
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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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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.
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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
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Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide. Amino Acids 2015; 47:2359-66. [DOI: 10.1007/s00726-015-2021-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 06/01/2015] [Indexed: 02/02/2023]
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Popovics P, Schally AV, Szalontay L, Block NL, Rick FG. Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating p21 and ROS levels. Oncotarget 2015; 5:4567-78. [PMID: 24994120 PMCID: PMC4147346 DOI: 10.18632/oncotarget.2146] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone (LHRH) analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108, consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog, AEZS-108, on LHRHR positive castration-resistant prostate cancer cells.
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Affiliation(s)
- Petra Popovics
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Cardiovascular Diseases, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL; Department of Medicine III, Medical Faculty Carl Gustav Carus, Dresden, Germany
| | - Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL; Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL; Endocrinology University of Miami, Miller School of Medicine, Miami, FL
| | - Luca Szalontay
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL
| | - Norman L Block
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL; Divisions of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL
| | - Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL
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Popovics P, Frigo DE, Schally AV, Rick FG. Targeting the 5'-AMP-activated protein kinase and related metabolic pathways for the treatment of prostate cancer. Expert Opin Ther Targets 2015; 19:617-32. [PMID: 25600663 DOI: 10.1517/14728222.2015.1005603] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Increasing evidence suggests that prostate cancer cells undergo unique metabolic reprogramming during transformation. A master regulator of cellular homeostasis, 5'-AMP-activated protein kinase (AMPK), directs metabolic adaptation that supports the growth demands of rapidly dividing cancer cells. The utilization of AMPK as a therapeutic target may therefore provide an effective strategy in the treatment of prostate cancer. AREAS COVERED Our review describes the regulation of AMPK by androgens and upstream kinases including the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in prostate cancer. Oncogenic, AMPK-regulated pathways that direct various metabolic processes are also addressed. Furthermore, we discuss the role of AMPK in growth arrest and autophagy as a potential survival pathway for cancer cells. In addition, by regulating non-metabolic pathways, AMPK may stimulate migration and mitosis. Finally, this review summarizes efforts to treat prostate cancer with pharmacological agents capable of modulating AMPK signaling. EXPERT OPINION Current research is primarily focused on developing drugs that activate AMPK as a treatment for prostate cancer. However, oncogenic aspects of AMPK signaling calls for caution about employing such therapies. We think that inhibitors of CaMKK2 or AMPK, or perhaps the modulation of downstream targets of AMPK, will gain importance in the clinical management of prostate cancer.
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Affiliation(s)
- Petra Popovics
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education , Research (151) 2A127, 1201 NW 16th St, Miami, FL 33125 , USA +1 305 5753477 ; +1 305 5753126 ;
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Rick FG, Schally AV. Bench-to-bedside development of agonists and antagonists of luteinizing hormone-releasing hormone for treatment of advanced prostate cancer. Urol Oncol 2014; 33:270-4. [PMID: 25512159 DOI: 10.1016/j.urolonc.2014.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/03/2014] [Accepted: 11/11/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Androgen deprivation therapy (ADT) has been the standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for 3 decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT. ADT AND LHRH ANALOGS The application of agonists of LHRH has improved and modernized the treatment of advanced PCa; millions of patients have benefited from therapy with LHRH agonists as a preferred alternative to surgical castration, as the psychological effects and perpetuity of orchiectomy are undesirable for most men. Despite their efficacy, agonists of LHRH have several shortcomings, including initial surge in testosterone, producing exacerbation of clinical symptoms, and microsurges in testosterone that might occur after each administration. A new, alternate approach to ADT is emerging with the improvements in antagonists of LHRH. This class of LHRH analogues produces a direct and immediate blockade of pituitary LHRH receptors and leads to a more rapid suppression of testosterone without an initial surge or subsequent microsurges. Degarelix, a third-generation LHRH antagonist, is the only antagonist with a low histamine-releasing activity that is currently on the market for clinical use in advanced PCa with improved testosterone suppression, better control of follicle-stimulating hormone and prostate-specific antigen, and which offers a prolonged delay to progression and more favorable effects on serum alkaline phosphatase. CONCLUSIONS Although LHRH agonists are still the mainstay for treatment of advanced PCa, antagonists of LHRH offer an alternative as a pharmacological approach.
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Affiliation(s)
- Ferenc G Rick
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL.
| | - Andrew V Schally
- Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL; Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL; Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL; Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL
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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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Abstract
The Nobel Prize in Physiology or Medicine was first awarded in 1901. Since then, the Nobel Prizes in Physiology or Medicine, Chemistry and Physics have been awarded to at least 33 distinguished researchers who were directly or indirectly involved in research into the field of endocrinology. This paper reflects on the life histories, careers and achievements of 11 of them: Frederick G Banting, Roger Guillemin, Philip S Hench, Bernardo A Houssay, Edward C Kendall, E Theodor Kocher, John J R Macleod, Tadeus Reichstein, Andrew V Schally, Earl W Sutherland, Jr and Rosalyn Yalow. All were eminent scientists, distinguished lecturers and winners of many prizes and awards.
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Affiliation(s)
- Wouter W de Herder
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
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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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