Related Experiment Video
Updated: Jun 11, 2025
Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts
Published on: April 26, 2018
The Fluorinated NAD Precursors Enhance FK866 Cytotoxicity by Activating SARM1 in Glioblastoma Cells
Wei Ming He1, Jian Yuan Yang2, Zhi Ying Zhao1
1State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
Abstract:
Glioblastoma, a formidable brain tumor characterized by dysregulated NAD metabolism, poses a significant therapeutic challenge. The NAMPT inhibitor FK866, which induces NAD depletion, has shown promise in controlling tumor proliferation and modifying the tumor microenvironment. However, the clinical efficacy of FK866 as a single drug therapy for glioma is limited. In this study, we aim to disrupt NAD metabolism using fluorinated NAD precursors and explore their synergistic effect with FK866 in inducing cytotoxicity in glioblastoma cells. The synthesized analogue of nicotinamide riboside (NR), ara-F nicotinamide riboside (F-NR), inhibits nicotinamide ribose kinase (NRK) activity in vitro, reduces cellular NAD levels, and enhances FK866's cytotoxicity in U251 glioblastoma cells, indicating a collaborative impact on cell death. Metabolic analyses reveal that F-NR undergoes conversion to fluorinated nicotinamide mononucleotide (F-NMN) and other metabolites, highlighting the intact NAD metabolic pathway in glioma cells. The activation of SARM1 by F-NMN, a potent NAD-consuming enzyme, is supported by the synergistic effect of CZ-48, a cell-permeable SARM1 activator. Temporal analysis underscores the sequential nature of events, establishing NAD depletion as a precursor to ATP depletion and eventual massive cell death. This study not only elucidates the molecular intricacies of glioblastoma cell death but also proposes a promising strategy to enhance FK866 efficacy through fluorinated NAD precursors, offering potential avenues for innovative therapeutic interventions in the challenging landscape of glioblastoma treatment.
Insights
Fluorinated nicotinamide riboside (F-NR) enhances the efficacy of FK866, a NAMPT inhibitor, by depleting NAD+ levels in glioblastoma cells. This combination strategy shows promise for improving glioblastoma treatment outcomes.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Glioblastoma exhibits dysregulated NAD+ metabolism, presenting a therapeutic challenge.
- The NAMPT inhibitor FK866 shows potential but has limited clinical efficacy as a monotherapy for glioma.
- Targeting NAD+ metabolism is a key strategy for glioblastoma treatment.
Purpose of the Study:
- To investigate the synergistic effect of fluorinated NAD+ precursors and FK866 in inducing glioblastoma cell death.
- To explore the molecular mechanisms underlying the enhanced cytotoxicity.
- To evaluate novel therapeutic strategies for glioblastoma.
Main Methods:
- Synthesis and characterization of ara-F nicotinamide riboside (F-NR), a fluorinated NAD+ precursor.
- In vitro assessment of F-NR's inhibition of nicotinamide ribose kinase (NRK) and cellular NAD+ levels.
- Evaluation of F-NR and FK866 combination therapy on U251 glioblastoma cell cytotoxicity.
- Metabolic analysis and SARM1 activation studies.
Main Results:
- F-NR inhibits NRK activity, reduces cellular NAD+ levels, and synergistically enhances FK866-induced cytotoxicity in glioblastoma cells.
- F-NR is converted to F-NMN, which activates the NAD+-consuming enzyme SARM1.
- NAD+ depletion precedes ATP depletion, leading to massive cell death.
- Combination therapy demonstrates a collaborative impact on glioblastoma cell death.
Conclusions:
- Fluorinated NAD+ precursors like F-NR can synergize with FK866 to enhance glioblastoma cell death.
- Disrupting NAD+ metabolism via F-NR and FK866 offers a promising therapeutic strategy for glioblastoma.
- This approach provides potential avenues for innovative glioblastoma treatment interventions.
