A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 12 2021
15 12 2021
Historique:
received:
29
01
2021
revised:
30
07
2021
accepted:
28
09
2021
pubmed:
2
10
2021
medline:
8
4
2022
entrez:
1
10
2021
Statut:
ppublish
Résumé
To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Identifiants
pubmed: 34593527
pii: 1078-0432.CCR-21-0374
doi: 10.1158/1078-0432.CCR-21-0374
pmc: PMC8678347
mid: NIHMS1746606
doi:
Substances chimiques
Nucleosides
0
Thionucleosides
0
alpha-2'-deoxythioguanosine
2133-81-5
Deoxyguanosine
G9481N71RO
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6800-6814Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136533
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA264385
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221675
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Neuro Oncol. 2016 Oct 1;18(suppl_5):v1-v75
pubmed: 28475809
Int J Radiat Oncol Biol Phys. 2019 Nov 15;105(4):861-874
pubmed: 31419512
Invest New Drugs. 2018 Dec;36(6):961-969
pubmed: 29508248
Cancer Res. 1988 Aug 1;48(15):4189-95
pubmed: 3390813
Mol Carcinog. 2019 Sep;58(9):1581-1588
pubmed: 31062416
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Genet. 2017 Mar;49(3):349-357
pubmed: 28135248
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Ups J Med Sci. 2012 May;117(2):99-112
pubmed: 22509804
Curr Opin Oncol. 1996 Jan;8(1):66-71
pubmed: 8868103
Int J Cancer. 2013 May 15;132(10):2339-48
pubmed: 23115013
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cancer Chemother Pharmacol. 1994;34(2):171-4
pubmed: 8194169
Nucleic Acids Res. 2002 May 15;30(10):e47
pubmed: 12000852
Mol Cancer Ther. 2018 Jul;17(7):1504-1514
pubmed: 29654065
Mol Cancer Res. 2013 Mar;11(3):219-29
pubmed: 23303345
Semin Neurol. 2018 Feb;38(1):50-61
pubmed: 29548052
Cancer Cell. 2018 Sep 10;34(3):513-528.e8
pubmed: 30205050
Oncoscience. 2015 Aug 22;2(8):693-5
pubmed: 26425659
Anticancer Agents Med Chem. 2011 Feb;11(2):202-12
pubmed: 21291403
Cancer Cell. 2020 Sep 14;38(3):400-411.e6
pubmed: 32619407
Asian Pac J Cancer Prev. ;18(1):3-9
pubmed: 28239999
Cancer Res. 2018 Jun 1;78(11):3002-3013
pubmed: 29531161
Cancer Discov. 2015 Jan;5(1):82-95
pubmed: 25516420
Cancer Chemother Pharmacol. 2001 Jul;48(1):83-7
pubmed: 11488529
Curr Protoc Pharmacol. 2011 Mar;Chapter 14:Unit 14.16
pubmed: 21743824
Clin Cancer Res. 2018 Oct 1;24(19):4771-4784
pubmed: 29563139
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Cesk Patol. 2008 Apr;44(2):35-6
pubmed: 18819324
J Neurooncol. 2013 Jan;111(2):97-102
pubmed: 23086436
Neoplasia. 2018 Aug;20(8):826-837
pubmed: 30015158
Expert Opin Ther Targets. 2018 Jul;22(7):599-613
pubmed: 29889582
Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6021-6
pubmed: 23530248
Science. 2015 May 29;348(6238):1036-9
pubmed: 25977370