Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines.
ACC cell lines
adrenocortical carcinoma
apoptosis
autophagy
invasion
metastasis
migration
progesterone
zebrafish model
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
06 Apr 2023
06 Apr 2023
Historique:
received:
26
02
2023
revised:
30
03
2023
accepted:
03
04
2023
medline:
14
4
2023
entrez:
13
4
2023
pubmed:
14
4
2023
Statut:
epublish
Résumé
Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.
Sections du résumé
BACKGROUND
BACKGROUND
Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers.
METHODS
METHODS
NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry.
RESULTS
RESULTS
Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells.
CONCLUSION
CONCLUSIONS
Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.
Identifiants
pubmed: 37047801
pii: ijms24076829
doi: 10.3390/ijms24076829
pmc: PMC10095539
pii:
doi:
Substances chimiques
Progesterone
4G7DS2Q64Y
Matrix Metalloproteinase 2
EC 3.4.24.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Italian Association for Cancer Research
ID : IG23009
Organisme : Italian Association for Cancer Research
ID : 27233
Références
JAMA. 2002 Jul 17;288(3):321-33
pubmed: 12117397
Altern Ther Health Med. 2017 Nov;23(6):24-32
pubmed: 29055286
Exp Cell Res. 2014 Apr 15;323(1):100-111
pubmed: 24589892
Future Oncol. 2020 Dec;16(36):3017-3020
pubmed: 32857613
J Steroid Biochem Mol Biol. 2009 Jan;113(1-2):75-9
pubmed: 19073257
Neurobiol Dis. 2013 Nov;59:80-5
pubmed: 23891729
BMC Cancer. 2017 Jun 20;17(1):434
pubmed: 28633655
Endocr Relat Cancer. 2005 Sep;12(3):657-66
pubmed: 16172198
Oncogene. 2003 Oct 9;22(44):6883-90
pubmed: 14534535
BMC Med Genet. 2011 May 31;12:78
pubmed: 21627810
Steroids. 2020 Sep;161:108680
pubmed: 32562708
Int Immunopharmacol. 2018 Jan;54:336-343
pubmed: 29197800
Front Oncol. 2021 Mar 12;11:620214
pubmed: 33777765
J Clin Oncol. 2012 Nov 10;30(32):3983-90
pubmed: 23008295
Oncol Rep. 2020 Jan;43(1):121-132
pubmed: 31746409
Cancer Res. 2018 Nov 1;78(21):6048-6058
pubmed: 30327381
Oncol Lett. 2019 Dec;18(6):6475-6482
pubmed: 31814847
Endocr Relat Cancer. 2022 Dec 22;30(2):
pubmed: 36449565
Int J Mol Sci. 2021 May 03;22(9):
pubmed: 34063734
Pharmaceutics. 2021 Oct 04;13(10):
pubmed: 34683909
J Steroid Biochem Mol Biol. 2015 Feb;146:62-73
pubmed: 24787660
Expert Opin Pharmacother. 2022 Aug;23(12):1413-1424
pubmed: 35876101
Cancer Biol Ther. 2011 Jan 15;11(2):169-76
pubmed: 21263212
Front Endocrinol (Lausanne). 2021 Apr 26;12:669426
pubmed: 33981288
Endocrine. 2022 Sep;77(3):432-437
pubmed: 35764904
Neurochem Int. 2012 Jan;60(2):125-33
pubmed: 22154800
Neoplasia. 2000 Jul-Aug;2(4):291-9
pubmed: 11005563
J Cell Sci. 2005 Jul 15;118(Pt 14):3091-102
pubmed: 15985464
Cells. 2022 Apr 24;11(9):
pubmed: 35563746
Biomaterials. 2016 Aug;97:34-50
pubmed: 27162073
Oncotarget. 2017 Nov 28;8(69):113583-113597
pubmed: 29371931
Int J Mol Sci. 2020 Dec 20;21(24):
pubmed: 33419373
Cell Oncol (Dordr). 2017 Aug;40(4):411-417
pubmed: 28653288
Ann Oncol. 2020 Nov;31(11):1476-1490
pubmed: 32861807
Cancers (Basel). 2020 Apr 10;12(4):
pubmed: 32290298
Clin Genitourin Cancer. 2021 Aug;19(4):316-324
pubmed: 33676835
Endocrine. 2019 Mar;63(3):592-601
pubmed: 30367443
Front Endocrinol (Lausanne). 2022 Jul 28;13:937367
pubmed: 35966083
Physiol Int. 2020 Oct 09;107(3):406-418
pubmed: 33074834
Oncotarget. 2016 Nov 29;7(48):79292-79304
pubmed: 27764813
Endocr Relat Cancer. 2008 Jun;15(2):465-74
pubmed: 18508999
Mol Cell Endocrinol. 2004 Dec 30;228(1-2):23-38
pubmed: 15541570
N Engl J Med. 2004 Jun 3;350(23):2417-9; author reply 2417-9
pubmed: 15179699
Eur Rev Med Pharmacol Sci. 2017 Oct;21(17):3959-3965
pubmed: 28975965
J Clin Endocrinol Metab. 2016 Dec;101(12):4594-4602
pubmed: 27626976
Endocrinology. 2022 Feb 1;163(2):
pubmed: 34875044
Cancers (Basel). 2021 Aug 20;13(16):
pubmed: 34439352
Mod Pathol. 2006 Dec;19(12):1563-9
pubmed: 16980949
N Engl J Med. 2012 Jun 7;366(23):2189-97
pubmed: 22551107