Document Type

Article

Publication Date

1-2024

Identifier

DOI: 10.1016/j.phrs.2023.106990

Abstract

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.

Journal Title

Pharmacological research : the official journal of the Italian Pharmacological Society

Volume

199

First Page

106990

Last Page

106990

MeSH Keywords

Humans; Glioblastoma; Antineoplastic Agents, Alkylating; Nucleosides; Caspases; Cell Line, Tumor; Temozolomide; Nucleotides; O(6)-Methylguanine-DNA Methyltransferase; Deoxyguanosine; DNA; Drug Resistance, Neoplasm; Polyphosphates

Keywords

DNA damage; GBM; O6-methyl-dGTP; Replication stress; TMZ

Comments

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.sciencedirect.com/science/article/pii/S1043661823003468?via%3Dihub

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