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Distinct capabilities in NAD metabolism mediate resistance to NAMPT inhibition in glioblastoma
File(s)
cancers-16-02054.pdf (4.38 MB)
Published version
Author(s)
Perryman, Richard
Chau, Tsz Wing
De-Felice, John
O’Neill, Kevin
Syed, Nelofer
Type
Journal Article
Abstract
Glioblastoma (GBM) cells require high levels of nicotinamide adenine dinucleotide (NAD) to fuel metabolic reactions, regulate their cell cycle and support DNA repair in response to chemotherapy and radiation. Inhibition of a key enzyme in NAD biosynthesis, NAMPT, has demonstrated significant anti-neoplastic activity. Here, we sought to characterise NAD biosynthetic pathways in GBM to determine resistance mechanisms to NAD inhibitors. GBM cells were treated with the NAMPT inhibitor FK866 with and without NAD precursors, and were analysed by qPCR, Western blot and proliferation assays (monolayer and spheroid). We also measured changes in the cell cycle, apoptosis, NAD/NADH levels and energy production. We performed orthoptic xenograft experiments in athymic nude mice to test the efficacy of FK866 in combination with temozolomide (TMZ). We show that the expression of key genes involved in NAD biosynthesis is highly variable across GBM tumours. FK866 inhibits proliferation, reduces NAD levels and limits oxidative metabolism, leading to G2/M cell cycle arrest; however, this can be reversed by supplementation with specific NAD precursors. Furthermore, FK866 potentiates the effects of radiation and TMZ in vitro and in vivo. NAMPT inhibitors should be considered for the treatment of GBM, with patients stratified based on their expression of key enzymes in other NAD biosynthetic pathways.
Date Issued
2024-06-01
Date Acceptance
2024-05-19
Citation
Cancers, 2024, 16 (11)
URI
URL
DOI
ISSN
2072-6694
Publisher
MDPI AG
Journal / Book Title
Cancers
Volume
16
Issue
11
Copyright Statement
© 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
License URL
Identifier
https://www.mdpi.com/2072-6694/16/11/2054
Publication Status
Published
Date Publish Online
2024-05-29