A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Document Type
Article
Publication Date
12-15-2021
Abstract
Purpose: To investigate the therapeutic role of a novel telomeredirected inhibitor, 6-thio-20-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. Experimental Design: 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 patientderived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. Results: 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. Conclusions: 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.
Identifier
85122397046 (Scopus)
Publication Title
Clinical Cancer Research
External Full Text Location
https://doi.org/10.1158/1078-0432.CCR-21-0374
e-ISSN
15573265
ISSN
10780432
PubMed ID
34593527
First Page
6800
Last Page
6814
Issue
24
Volume
27
Grant
R01CA136533
Fund Ref
National Institutes of Health
Recommended Citation
Yu, Shengnan; Wei, Shiyou; Savani, Milan; Lin, Xiang; Du, Kuang; Mender, Ilgen; Siteni, Silvia; Vasilopoulos, Themistoklis; Reitman, Zachary J.; Ku, Yin; Wu, Di; Liu, Hao; Tian, Meng; Chen, Yaohui; Labrie, Marilyne; Charbonneau, Casey M.; Sugarman, Eric; and Bowie, Michelle, "A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas" (2021). Faculty Publications. 3584.
https://digitalcommons.njit.edu/fac_pubs/3584
