TY - JOUR
T1 - A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas
AU - Yu, Shengnan
AU - Wei, Shiyou
AU - Savani, Milan
AU - Lin, Xiang
AU - Du, Kuang
AU - Mender, Ilgen
AU - Siteni, Silvia
AU - Vasilopoulos, Themistoklis
AU - Reitman, Zachary J.
AU - Ku, Yin
AU - Wu, Di
AU - Liu, Hao
AU - Tian, Meng
AU - Chen, Yaohui
AU - Labrie, Marilyne
AU - Charbonneau, Casey M.
AU - Sugarman, Eric
AU - Bowie, Michelle
AU - Hariharan, Seethalakshmi
AU - Waitkus, Matthew
AU - Jiang, Wen
AU - McLendon, Roger E.
AU - Pan, Edward
AU - Khasraw, Mustafa
AU - Walsh, Kyle M.
AU - Lu, Yiling
AU - Herlyn, Meenhard
AU - Mills, Gordon
AU - Herbig, Utz
AU - Wei, Zhi
AU - Keir, Stephen T.
AU - Flaherty, Keith
AU - Liu, Lunxu
AU - Wu, Kongming
AU - Shay, Jerry W.
AU - Abdullah, Kalil
AU - Zhang, Gao
AU - Ashley, David M.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-0374
DO - 10.1158/1078-0432.CCR-21-0374
M3 - Article
C2 - 34593527
AN - SCOPUS:85122397046
SN - 1078-0432
VL - 27
SP - 6800
EP - 6814
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -