Pharmacol Res. 2024 Jan:199:106990.doi: 10.1016/j.phrs.2023.106990. Epub 2023 Nov 18. (IF:10.334).

本文采用的英格恩产品: RNA-Entranster-invivo

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

Affiliations

Affiliations

  • 1 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 2 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China.
  • 3 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 5 Wu Xi AppTec (Tianjin) Co., Ltd, China.
  • 6 Children’s Mercy Research Institute, Kansas City, MO 64108, USA.
  • 7 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. Electronic address: caijp61@vip.sina.com.

Free article

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.

Keywords: DNA damage; GBM; O6-methyl-dGTP; Replication stress; TMZ.

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