A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
Shengnan Yu1,2,3,4, Shiyou Wei1,2,5, Milan Savani6
1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
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.
Insights
The novel telomere-directed inhibitor 6-thio-2'-deoxyguanosine (THIO) shows therapeutic potential against gliomas by inducing DNA damage and apoptosis. THIO demonstrated efficacy in various glioma models, including those resistant to temozolomide, with minimal toxicity to normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gliomas are aggressive brain tumors with limited treatment options.
- Telomere maintenance is crucial for cancer cell proliferation and survival.
- Novel therapeutic strategies targeting telomeres are needed for glioma treatment.
Purpose of the Study:
- To evaluate the therapeutic efficacy of 6-thio-2 -deoxyguanosine (THIO), a novel telomere-directed inhibitor, in glioma models.
- To elucidate the antitumor mechanisms of THIO in gliomas.
- To assess the safety and efficacy of THIO in both in vitro and in vivo settings.
Main Methods:
- Utilized human and mouse glioma cell lines for in vitro efficacy testing via cell viability assays, flow cytometry, and immunofluorescence.
- Conducted integrated analyses of RNA sequencing and reverse-phase protein array data to identify antitumor mechanisms.
- Employed patient-derived xenografts (PDX), patient-derived organoids (PDO), and xenografts of human glioma cell lines for in vivo validation.
Main Results:
- THIO exhibited efficacy in most glioma cell lines with no significant toxicity to normal astrocytes.
- THIO demonstrated effectiveness as a monotherapy in temozolomide-resistant glioma cells.
- THIO induced telomeric DNA damage and apoptosis in glioma cells and tumor models, inhibiting invasion, stemness, and proliferation pathways.
Conclusions:
- Established the therapeutic role of THIO in primary and recurrent gliomas.
- Identified acute induction of telomeric DNA damage as a key antitumor mechanism of THIO.
- THIO presents a promising therapeutic agent for glioma treatment, warranting further clinical investigation.
