A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

Journal Article (Journal Article)

Purpose

To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-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 patient-derived 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.

Full Text

Duke Authors

Cited Authors

  • Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM

Published Date

  • December 2021

Published In

Volume / Issue

  • 27 / 24

Start / End Page

  • 6800 - 6814

PubMed ID

  • 34593527

Pubmed Central ID

  • PMC8678347

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.ccr-21-0374

Language

  • eng