Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment.
Artemesia annua
artesunate
carboplatin
dihydroartemisinin
ovarian cancer
paclitaxel
Journal
Diagnostics (Basel, Switzerland)
ISSN: 2075-4418
Titre abrégé: Diagnostics (Basel)
Pays: Switzerland
ID NLM: 101658402
Informations de publication
Date de publication:
26 Feb 2021
26 Feb 2021
Historique:
received:
01
12
2020
revised:
22
02
2021
accepted:
24
02
2021
entrez:
3
3
2021
pubmed:
4
3
2021
medline:
4
3
2021
Statut:
epublish
Résumé
Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment. Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq analysis was utilized to identify genes and the associated genetic pathways that were differentially regulated in artesunate resistant organoid models compared to organoids that were sensitive to artesunate. Artesunate treatment reduces cell viability in 2D and 3D ovarian cancer cell models. Clinically relevant concentrations of artesunate induce G1 arrest, but do not induce DNA damage. Pathways related to cell cycle progression, specifically G1/S transition, are upregulated in ovarian organoid models that are innately more resistant to artesunate compared to more sensitive models. Depending on the sequence of administration, the addition of artesunate to carboplatin and paclitaxel improves their effectiveness. Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment.
METHODS
METHODS
Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq analysis was utilized to identify genes and the associated genetic pathways that were differentially regulated in artesunate resistant organoid models compared to organoids that were sensitive to artesunate.
RESULTS
RESULTS
Artesunate treatment reduces cell viability in 2D and 3D ovarian cancer cell models. Clinically relevant concentrations of artesunate induce G1 arrest, but do not induce DNA damage. Pathways related to cell cycle progression, specifically G1/S transition, are upregulated in ovarian organoid models that are innately more resistant to artesunate compared to more sensitive models. Depending on the sequence of administration, the addition of artesunate to carboplatin and paclitaxel improves their effectiveness.
CONCLUSIONS
CONCLUSIONS
Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer.
Identifiants
pubmed: 33652561
pii: diagnostics11030395
doi: 10.3390/diagnostics11030395
pmc: PMC7996621
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA160003
Pays : United States
Références
Gynecol Oncol. 2019 Jul;154(1):189-198
pubmed: 31101504
Nat Commun. 2015 Dec 08;6:8989
pubmed: 26643275
N Engl J Med. 2011 Dec 29;365(26):2473-83
pubmed: 22204724
Med Sci (Basel). 2018 Feb 27;6(1):
pubmed: 29495461
Acta Pharmacol Sin. 2007 Jul;28(7):1045-56
pubmed: 17588342
N Engl J Med. 1996 Jan 4;334(1):1-6
pubmed: 7494563
Int J Parasitol. 2006 Dec;36(14):1427-41
pubmed: 17005183
Semin Cancer Biol. 2017 Oct;46:65-83
pubmed: 28254675
Braz J Med Biol Res. 2019;52(5):e7992
pubmed: 31038546
Chem Commun (Camb). 2018 Oct 16;54(83):11717-11720
pubmed: 30229259
Mol Cancer Ther. 2011 Dec;10(12):2224-33
pubmed: 21998290
Life Sci. 2020 Feb 1;242:117221
pubmed: 31881224
Nat Prod Bioprospect. 2014 Jun;4(3):189-96
pubmed: 24955301
Cancer Chemother Pharmacol. 2004 May;53(5):423-32
pubmed: 15132130
J Biomed Biotechnol. 2012;2012:247597
pubmed: 22174561
ACS Chem Biol. 2019 Apr 19;14(4):636-643
pubmed: 30840434
Mol Carcinog. 2017 Jan;56(1):75-93
pubmed: 26878598
Cancer Chemother Pharmacol. 2016 Feb;77(2):413-27
pubmed: 26793976
Cancer Biol Ther. 2015;16(10):1548-56
pubmed: 26176175
Oncotarget. 2016 May 31;7(22):32810-20
pubmed: 27147568
Cancer Chemother Pharmacol. 2018 Mar;81(3):587-596
pubmed: 29392450
Genome Biol. 2010;11(2):R14
pubmed: 20132535
Mol Pharmacol. 2003 Aug;64(2):382-94
pubmed: 12869643
Phytomedicine. 2019 Feb 15;54:140-148
pubmed: 30668363
Cancer Med. 2018 Nov;7(11):5704-5715
pubmed: 30338663
Malar J. 2012 Apr 27;11:132
pubmed: 22540954
Anticancer Res. 2017 Nov;37(11):5995-6003
pubmed: 29061778
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Cancer Discov. 2018 Nov;8(11):1404-1421
pubmed: 30213835
N Engl J Med. 2018 Dec 27;379(26):2495-2505
pubmed: 30345884
Fundam Clin Pharmacol. 2017 Jun;31(3):301-310
pubmed: 28078787
J Clin Oncol. 2003 Sep 1;21(17):3194-200
pubmed: 12860964