A Modified Nucleoside 6-thio-2'-deoxyguanosine Exhibits Anti-tumor Activity in Gliomas.

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 were 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 anti-tumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoid (PDOs) 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 TMZ. In addition, THIO showed efficacy in 4 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 GBM 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 anti-tumor mechanism of THIO in gliomas.