Pharmacological Research (Jan 2024)

A modified nucleoside O6-methyl-2′-deoxyguanosine-5′-triphosphate exhibits anti-glioblastoma activity in a caspase-independent manner

  • Zi-Hui Wang,
  • Jin Li,
  • Qian Liu,
  • Jian-Chang Qian,
  • Qing-Qing Li,
  • Qing-Yu Wang,
  • Lv-Tao Zeng,
  • Si-Jia Li,
  • Xin Gao,
  • Jia-Xin Pan,
  • Xu-Fan Gao,
  • Kun Wu,
  • Guo-Xin Hu,
  • Tomoo Iwakuma,
  • Jian-Ping Cai

Journal volume & issue
Vol. 199
p. 106990

Abstract

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Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2′-deoxyguanosine-5′-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.

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