Growth hormone-releasing hormone and cancer.
Cancer therapy
GHRH agonists
GHRH antagonists
GHRH receptors
Signaling pathways
Journal
Reviews in endocrine & metabolic disorders
ISSN: 1573-2606
Titre abrégé: Rev Endocr Metab Disord
Pays: Germany
ID NLM: 100940588
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
accepted:
14
10
2024
medline:
18
10
2024
pubmed:
18
10
2024
entrez:
18
10
2024
Statut:
aheadofprint
Résumé
The hypothalamic hormone growth hormone-releasing hormone (GHRH), in addition to promoting the synthesis and release of growth hormone (GH), stimulates the proliferation of human normal and malignant cells by binding to GHRH-receptor (GHRH-R) and its main splice variant, SV1. Both GHRH and GHRH-Rs are expressed in various cancers, forming a stimulatory pathway for cancer cell growth; additionally, SV1 possesses ligand independent proliferative effects. Therefore, targeting GHRH-Rs pharmacologically has been proposed for the treatment of cancer. Various classes of synthetic GHRH antagonists have been developed, endowed with strong anticancer activity in vitro and in vivo, in addition to displaying anti-inflammatory, antioxidant and immune-modulatory functions. GHRH antagonists exert indirect effects by blocking the pituitary GH/hepatic insulin-like growth factor I (IGF-I) axis, or directly inhibiting the binding of GHRH on tumor GHRH-Rs. Additionally, GHRH antagonists block the mitogenic functions of SV1 in tumor cells. This review illustrates the main findings on the antitumor effects of GHRH antagonists in experimental human cancers, along with their underlying mechanisms. The development of GHRH antagonists, with reduced toxicity and high stability, could lead to novel therapeutic agents for the treatment of cancer and inflammatory diseases.
Identifiants
pubmed: 39422787
doi: 10.1007/s11154-024-09919-4
pii: 10.1007/s11154-024-09919-4
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : #20223WSTY4
Organisme : BENEFICENTIA Stiftung Foundation
ID : 2023/20
Organisme : CRT Foundation 2023
ID : #106459
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Barabutis N, Schally AV. Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer line. Proc Natl Acad Sci U S A. 2008;105(51):20470–5. https://doi.org/10.1073/pnas.0811209106 .
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Munoz-Moreno L, Arenas MI, Carmena MJ, Schally AV, Sanchez-Chapado M, Prieto JC, Bajo AM. Anti-proliferative and pro-apoptotic effects of GHRH antagonists in prostate cancer. Oncotarget. 2016;7(32):52195–206. https://doi.org/10.18632/oncotarget.10710 .
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Fahrenholtz CD, Rick FG, Garcia MI, Zarandi M, Cai RZ, Block NL, Schally AV, Burnstein KL. 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(3):1084–9. https://doi.org/10.1073/pnas.1323102111 .
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Munoz-Moreno L, Schally AV, Prieto JC, Carmena MJ, Bajo AM. Growth hormone-releasing hormone receptor antagonists modify molecular machinery in the progression of prostate cancer. Prostate. 2018;78(12):915–26. https://doi.org/10.1002/pros.23648 .
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Busto R, Schally AV, Varga JL, Garcia-Fernandez MO, Groot K, Armatis P, Szepeshazi K. The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas. Proc Natl Acad Sci U S A. 2002;99(18):11866–71. https://doi.org/10.1073/pnas.182433099 .
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Gan J, Ke X, Jiang J, Dong H, Yao Z, Lin Y, Lin W, Wu X, Yan S, Zhuang Y, Chu WK, Cai R, Zhang X, Cheung HS, Block NL, Pang CP, Schally AV, Zhang H. Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1-STAT3/NF-kappaB signaling. Proc Natl Acad Sci U S A. 2016;113(51):14745–50. https://doi.org/10.1073/pnas.1618582114 .
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Hohla F, Moder A, Mayrhauser U, Hauser-Kronberger C, Schally AV, Varga JL, Zarandi M, Buchholz S, Huber R, Aigner E, Ritter M, Datz C. Differential expression of GHRH receptor and its splice variant 1 in human normal and malignant mucosa of the oesophagus and colon. Int J Oncol. 2008;33(1):137–43.
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Fodor D, Pozsgai E, Schally AV, Laszlo Z, Gomori E, Szabo E, Rumi L, Locsei D, Boronkai A, Bellyei S. Expression levels of GHRH-Receptor, pAkt and Hsp90 predict 10-year overall survival in patients with locally advanced rectal cancer. Biomedicines. 2023;11(3):719. https://doi.org/10.3390/biomedicines11030719 .
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Szepeshazi K, Schally AV, Groot K, Armatis P, Halmos G, Herbert F, Szende B, Varga JL, Zarandi M. Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers. Br J Cancer. 2000;82(10):1724–31. https://doi.org/10.1054/bjoc.2000.1223 .
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Hohla F, Buchholz S, Schally AV, Seitz S, Rick FG, Szalontay L, Varga JL, Zarandi M, Halmos G, Vidaurre I, Krishan A, Kurtoglu M, Chandna S, Aigner E, Datz C. GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells. Cell Cycle. 2009;8(19):3149–56. https://doi.org/10.4161/cc.8.19.9698 .
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Recinella L, Chiavaroli A, Veschi S, Di Valerio V, Lattanzio R, Orlando G, Ferrante C, Gesmundo I, Granata R, Cai R, Sha W, Schally AV, Brunetti L, Leone S. Antagonist of growth hormone-releasing hormone MIA-690 attenuates the progression and inhibits growth of colorectal cancer in mice. Biomed Pharmacother. 2022;146:112554. https://doi.org/10.1016/j.biopha.2021.112554 .
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Annunziata M, Grande C, Scarlatti F, Deltetto F, Delpiano E, Camanni M, Ghigo E, Granata R. The growth hormone-releasing hormone (GHRH) antagonist JV-1-36 inhibits proliferation and survival of human ectopic endometriotic stromal cells (ESCs) and the T HESC cell line. Fertil Steril. 2010;94(3):841–9. https://doi.org/10.1016/j.fertnstert.2009.03.093 .
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Fu L, Osuga Y, Yano T, Takemura Y, Morimoto C, Hirota Y, Schally AV, Taketani Y. Expression and possible implication of growth hormone-releasing hormone receptor splice variant 1 in endometriosis. Fertil Steril. 2009;92(1):47–53. https://doi.org/10.1016/j.fertnstert.2008.04.048 .
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Kahan Z, Arencibia JM, Csernus VJ, Groot K, Kineman RD, Robinson WR, Schally AV. Expression of growth hormone-releasing hormone (GHRH) messenger ribonucleic acid and the presence of biologically active GHRH in human breast, endometrial, and ovarian cancers. J Clin Endocrinol Metab. 1999;84(2):582–9. https://doi.org/10.1210/jcem.84.2.5487 .
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Szabo Z, Juhasz E, Schally AV, Dezso B, Huga S, Hernadi Z, Halmos G, Kiss C. Expression of growth hormone-releasing hormone and its receptor splice variants in primary human endometrial carcinomas: novel therapeutic approaches. Molecules. 2022;27(9):2671. https://doi.org/10.3390/molecules27092671 .
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Wu HM, Huang HY, Schally AV, Chao A, Chou HH, Leung PC, Wang HS. Growth hormone-releasing hormone antagonist inhibits the invasiveness of human endometrial cancer cells by down-regulating twist and N-cadherin expression. Oncotarget. 2017;8(3):4410–21. https://doi.org/10.18632/oncotarget.13877 .
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Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9. https://doi.org/10.1016/j.fertnstert.2012.06.029 .
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Koster F, Jin L, Shen Y, Schally AV, Cai RZ, Block NL, Hornung D, Marschner G, Rody A, Engel JB, Finas D. Effects of an antagonistic analog of growth hormone-releasing hormone on endometriosis in a mouse model and in vitro. Reprod Sci. 2017;24(11):1503–11. https://doi.org/10.1177/1933719117691140 .
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Wu HM, Chen LH, Schally AV, Huang HY, Soong YK, Leung PCK, Wang HS. Impact of growth hormone-releasing hormone antagonist on decidual stromal cell growth and apoptosis in vitrodagger. Biol Reprod. 2022;106(1):145–54. https://doi.org/10.1093/biolre/ioab214 .
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Guo J, Schally AV, Zarandi M, Varga J, Leung PC. Antiproliferative effect of growth hormone-releasing hormone (GHRH) antagonist on ovarian cancer cells through the EGFR-Akt pathway. Reprod Biol Endocrinol. 2010;8:54. https://doi.org/10.1186/1477-7827-8-54 .
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Papadia A, Schally AV, Halmos G, Varga JL, Seitz S, Buchholz S, Rick F, Zarandi M, Bellyei S, Treszl A, Szalontay L, Lucci JA. Growth hormone-releasing hormone antagonists inhibit growth of human ovarian cancer. Horm Metab Res. 2011;43(11):816–20. https://doi.org/10.1055/s-0031-1287766 .
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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. 2012;118(3):670–80. https://doi.org/10.1002/cncr.26291 .
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Chale RS, Almeida SM, Rodriguez M, Jozic I, Gaumond SI, Schally AV, Jimenez JJ. The application of GHRH antagonist as a treatment for resistant APL. Cancers (Basel). 2023;15(12):3104. https://doi.org/10.3390/cancers15123104 .
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Jimenez JJ, DelCanto GM, Popovics P, Perez A, Vila Granda A, Vidaurre I, Cai RZ, Rick FG, Swords RT, Schally AV. A new approach to the treatment of acute myeloid leukaemia targeting the receptor for growth hormone-releasing hormone. Br J Haematol. 2018;181(4):476–85. https://doi.org/10.1111/bjh.15207 .
doi: 10.1111/bjh.15207
Juhasz E, Szabo Z, Schally AV, Kiraly J, Fodor P, Konya G, Dezso B, Szabo E, Halmos G, Kiss C. Expression of growth hormone-releasing hormone and its receptor splice variants in a cohort of hungarian pediatric patients with hematological and oncological disorders: a pilot study. Int J Mol Sci. 2024;25(16):8831. https://doi.org/10.3390/ijms25168831 .
Keller G, Schally AV, Groot K, Toller GL, Havt A, Koster F, Armatis P, Halmos G, Zarandi M, Varga JL, Engel JB. Effective treatment of experimental human non-Hodgkin’s lymphomas with antagonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A. 2005;102(30):10628–33. https://doi.org/10.1073/pnas.0504102102 .
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Jaeger LB, Banks WA, Varga JL, Schally AV. Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumors. Proc Natl Acad Sci U S A. 2005;102(35):12495–500. https://doi.org/10.1073/pnas.0504163102 .
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Recinella L, Chiavaroli A, Orlando G, Ferrante C, Marconi GD, Gesmundo I, Granata R, Cai R, Sha W, Schally AV, Brunetti L, Leone S. Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice. Sci Rep. 2020;10(1):732. https://doi.org/10.1038/s41598-019-57292-z .
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Jaszberenyi M, Rick FG, Popovics P, Block NL, Zarandi M, Cai RZ, Vidaurre I, Szalontay L, Jayakumar AR, Schally AV. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists. Proc Natl Acad Sci U S A. 2014;111(2):781–6. https://doi.org/10.1073/pnas.1322622111 .
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Chang Y, Huang R, Zhai Y, Huang L, Feng Y, Wang D, Chai R, Zhang W, Hu H. A potentially effective drug for patients with recurrent glioma: sermorelin. Ann Transl Med. 2021;9(5):406. https://doi.org/10.21037/atm-20-6561 .
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Schaff LR, Mellinghoff IK. Glioblastoma and other primary brain malignancies in adults: a review. JAMA. 2023;329(7):574–87. https://doi.org/10.1001/jama.2023.0023 .
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Mezey G, Treszl A, Schally AV, Block NL, Vizkeleti L, Juhasz A, Klekner A, Nagy J, Balazs M, Halmos G, Bognar L. Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes. J Cancer Res Clin Oncol. 2014;140(10):1641–9. https://doi.org/10.1007/s00432-014-1716-1 .
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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(4):281–90. https://doi.org/10.1007/s11523-013-0264-y .
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pubmed: 23371031
Pozsgai E, Schally AV, Zarandi M, Varga JL, Vidaurre I, Bellyei S. The effect of GHRH antagonists on human glioblastomas and their mechanism of action. Int J Cancer. 2010;127(10):2313–22. https://doi.org/10.1002/ijc.25259 .
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pubmed: 20162575
Qin YJ, Chan SO, Chong KK, Li BF, Ng TK, Yip YW, Chen H, Zhang M, Block NL, Cheung HS, Schally AV, Pang CP. Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation. Proc Natl Acad Sci U S A. 2014;111(51):18303–8. https://doi.org/10.1073/pnas.1421815112 .
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Chu WK, Law KS, Chan SO, Yam JC, Chen LJ, Zhang H, Cheung HS, Block NL, Schally AV, Pang CP. Antagonists of growth hormone-releasing hormone receptor induce apoptosis specifically in retinoblastoma cells. Proc Natl Acad Sci U S A. 2016;113(50):14396–401. https://doi.org/10.1073/pnas.1617427113 .
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Gesmundo I, Granato G, Fuentes-Fayos AC, Alvarez CV, Dieguez C, Zatelli MC, Congiusta N, Banfi D, Prencipe N, Leone S, Brunetti L, Castano JP, Luque RM, Cai R, Sha W, Ghigo E, Schally AV, Granata R. Antagonists of growth hormone-releasing hormone inhibit the growth of pituitary adenoma cells by hampering oncogenic pathways and promoting apoptotic signaling. Cancers (Basel). 2021;13(16):3950. https://doi.org/10.3390/cancers13163950 .
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Catanuto P, Tashiro J, Rick FG, Sanchez P, Solorzano CC, Glassberg MK, Block NL, Lew JI, Elliot SJ, Schally AV. 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. Horm Cancer. 2015;6(2–3):100–6. https://doi.org/10.1007/s12672-015-0217-2 .
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Populo H, Nunes B, Sampaio C, Batista R, Pinto MT, Gaspar TB, Miranda-Alves L, Cai RZ, Zhang XY, Schally AV, Sobrinho-Simoes M, Soares P. Inhibitory effects of antagonists of growth hormone-releasing hormone (GHRH) in thyroid cancer. Horm Cancer. 2017;8(5–6):314–24. https://doi.org/10.1007/s12672-017-0307-4 .
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Ziegler CG, Brown JW, Schally AV, Erler A, Gebauer L, Treszl A, Young L, Fishman LM, Engel JB, Willenberg HS, Petersenn S, Eisenhofer G, Ehrhart-Bornstein M, Bornstein SR. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci U S A. 2009;106(37):15879–84. https://doi.org/10.1073/pnas.0907843106 .
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Ziegler CG, Ullrich M, Schally AV, Bergmann R, Pietzsch J, Gebauer L, Gondek K, Qin N, Pacak K, Ehrhart-Bornstein M, Eisenhofer G, Bornstein SR. Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells. Mol Cell Endocrinol. 2013;371(1–2):189–94. https://doi.org/10.1016/j.mce.2012.12.011 .
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Belavgeni A, Bornstein SR, von Massenhausen A, Tonnus W, Stumpf J, Meyer C, Othmar E, Latk M, Kanczkowski W, Kroiss M, Hantel C, Hugo C, Fassnacht M, Ziegler CG, Schally AV, Krone NP, Linkermann A. Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(44):22269–74. https://doi.org/10.1073/pnas.1912700116 .
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Chatzistamou I, Volakaki AA, Schally AV, Kiaris H, Kittas C. Expression of growth hormone-releasing hormone receptor splice variant 1 in primary human melanomas. Regul Pept. 2008;147(1–3):33–6. https://doi.org/10.1016/j.regpep.2007.12.008 .
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pubmed: 18255167
Szalontay L, Schally AV, Popovics P, Vidaurre I, Krishan A, Zarandi M, Cai RZ, Klukovits A, Block NL, Rick FG. Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function. Cell Cycle. 2014;13(17):2790–7. https://doi.org/10.4161/15384101.2015.945879 .
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Halmos G, Schally AV, Bernardino AL, Varga JL. Characterization of receptors for growth hormone-releasing hormone in human osteosarcomas and Ewing’s sarcomas. Int J Oncol. 2006;29(2):463–9.
pubmed: 16820890
Braczkowski R, Schally AV, Plonowski A, Varga JL, Groot K, Krupa M, Armatis P. Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: effects on insulin-like growth factor II. Cancer. 2002;95(8):1735–45. https://doi.org/10.1002/cncr.10865 .
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Kiaris H, Chatzistamou I. Inhibition of tumor growth by agonists of growth hormone-releasing hormone. Proc Natl Acad Sci U S A. 2018;115(47):11876–8. https://doi.org/10.1073/pnas.1817342115 .
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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(9):1036–54. https://doi.org/10.1002/pros.23360 .
doi: 10.1002/pros.23360
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Cui T, Schally AV. Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1. Oncotarget. 2018;9(47):28745–56. https://doi.org/10.18632/oncotarget.25676 .
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