Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Disease Models, Animal
Gene Expression
Growth Hormone-Releasing Hormone
/ antagonists & inhibitors
Humans
Lung Neoplasms
/ drug therapy
Mesothelioma
/ drug therapy
Mesothelioma, Malignant
Mice
Mitochondria
/ drug effects
Pleural Neoplasms
/ drug therapy
Receptors, Neuropeptide
/ genetics
Receptors, Pituitary Hormone-Regulating Hormone
/ genetics
Xenograft Model Antitumor Assays
GHRH antagonists
GHRH receptor
growth hormone-releasing hormone
malignant pleural mesothelioma
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
05 02 2019
05 02 2019
Historique:
pubmed:
20
1
2019
medline:
17
4
2019
entrez:
20
1
2019
Statut:
ppublish
Résumé
Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.
Identifiants
pubmed: 30659154
pii: 1818865116
doi: 10.1073/pnas.1818865116
pmc: PMC6369772
doi:
Substances chimiques
Antineoplastic Agents
0
GHRHR protein, human
0
Receptors, Neuropeptide
0
Receptors, Pituitary Hormone-Regulating Hormone
0
Growth Hormone-Releasing Hormone
9034-39-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2226-2231Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Conflict of interest statement: A.V.S. and R.C. are listed as co-inventors on the patent for GHRH agonists, assigned to the University of Miami, Miami, FL, and the Veterans Affairs Medical Center, Miami, FL. The remaining authors declare no conflict of interest.
Références
Arch Pathol Lab Med. 2018 Jan;142(1):89-108
pubmed: 28686500
Cancer Res. 2004 Oct 15;64(20):7479-85
pubmed: 15492273
Carcinogenesis. 2013 Jul;34(7):1413-9
pubmed: 23677068
Nat Clin Pract Endocrinol Metab. 2008 Jan;4(1):33-43
pubmed: 18084344
Cell Cycle. 2009 Oct 1;8(19):3149-56
pubmed: 19755849
Horm Cancer. 2017 Dec;8(5-6):314-324
pubmed: 28924876
Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):12028-12033
pubmed: 30373845
J Pathol. 2001 Apr;193(4):468-75
pubmed: 11276005
Cancer. 2012 Feb 1;118(3):670-80
pubmed: 21751186
Br J Haematol. 2018 May;181(4):476-485
pubmed: 29663325
Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3755-60
pubmed: 21321192
Peptides. 2017 Mar;89:60-70
pubmed: 28130121
J Endocrinol Invest. 2016 Jul;39(7):721-7
pubmed: 26891937
Oncotarget. 2018 Jun 19;9(47):28745-28756
pubmed: 29983893
Prostate. 2018 Sep;78(13):970-980
pubmed: 29786867
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14894-8
pubmed: 10611309
J Thorac Oncol. 2018 Sep;13(9):1269-1283
pubmed: 29966799
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5575-9
pubmed: 17372203
Cancer Lett. 2010 Dec 1;298(1):16-25
pubmed: 20630651
Prostate. 2012 Apr;72(5):555-65
pubmed: 21796649
Cancer Res. 2003 Nov 15;63(22):7913-9
pubmed: 14633721
Eur Respir Rev. 2016 Dec;25(142):472-486
pubmed: 27903668
Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14396-14401
pubmed: 27911838
Nat Rev Cancer. 2014 Nov;14(11):709-21
pubmed: 25342630
Am J Cancer Res. 2017 Aug 01;7(8):1724-1737
pubmed: 28861328
Int J Cancer. 2010 Nov 15;127(10):2313-22
pubmed: 20162575
Trends Endocrinol Metab. 2011 Aug;22(8):311-7
pubmed: 21530304
EBioMedicine. 2018 Nov;37:557-562
pubmed: 30344124
Cardiovasc Res. 2009 Jul 15;83(2):303-12
pubmed: 19293247
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2604-9
pubmed: 20133784
Oncotarget. 2016 Aug 16;7(33):52661-52672
pubmed: 27494841
Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13651-6
pubmed: 26474831
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14745-14750
pubmed: 27930339
Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):12033-12038
pubmed: 29078377
Endocrinology. 2015 Sep;156(9):3239-52
pubmed: 26110916
Int J Cancer. 2018 Jun 1;142(11):2394-2404
pubmed: 29435973
Cell Cycle. 2010 Oct 15;9(20):4110-6
pubmed: 20962577
Oncotarget. 2016 Nov 22;7(47):76577-76589
pubmed: 27391433
Lung Cancer. 2018 Jun;120:34-45
pubmed: 29748013
Cancer Res. 2010 Jan 15;70(2):440-6
pubmed: 20068163
Semin Cancer Biol. 2017 Dec;47:29-42
pubmed: 28655520
J Cell Physiol. 2018 Nov;233(11):8952-8961
pubmed: 29904909
Cell Death Dis. 2014 Apr 10;5:e1167
pubmed: 24722292
Oncol Rep. 2015 May;33(5):2411-9
pubmed: 25738249
Prostate. 2018 Sep;78(12):915-926
pubmed: 29748961
Peptides. 2012 Sep;37(1):63-8
pubmed: 22819774
J Thorac Oncol. 2013 Nov;8(11):1389-95
pubmed: 24084442