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A Modified Nucleoside 6-thio-2’-deoxyguanosine Exhibits Anti-tumor Activity in Gliomas
- Source :
- Clin Cancer Res
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Proteomics
Cancer Research
Thionucleosides
Chemistry
DNA damage
Brain Neoplasms
Thio
Deoxyguanosine
Nucleosides
Glioma
Xenograft Model Antitumor Assays
Article
chemistry.chemical_compound
Mice
Oncology
Apoptosis
In vivo
Cell culture
Cell Line, Tumor
Cancer research
Animals
Humans
Viability assay
Stem cell
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Clin Cancer Res
- Accession number :
- edsair.doi.dedup.....f6aee3a60fc3803eb740dc2c3bb2bb99