The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1 -Mutant Cancers and Potentiates NAD + Depletion-Mediated Cytotoxicity

-mutant gliomas are dependent upon the canonical coenzyme NAD for survival. It is known that PARP activation consumes NAD during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD biosynthesis inhibitors with the alkylating chemothe...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-08, Vol.77 (15), p.4102-4115
Main Authors: Tateishi, Kensuke, Higuchi, Fumi, Miller, Julie J, Koerner, Mara V A, Lelic, Nina, Shankar, Ganesh M, Tanaka, Shota, Fisher, David E, Batchelor, Tracy T, Iafrate, A John, Wakimoto, Hiroaki, Chi, Andrew S, Cahill, Daniel P
Format: Article
Language:English
Subjects:
Acrylamides - pharmacology
Activation
Alkylation
Animals
Antineoplastic Agents, Alkylating - pharmacology
Base excision repair
Biosynthesis
Cancer
Cancer therapies
Cell Line, Tumor
Cell lines
Chemotherapy
Cytotoxicity
Dacarbazine - analogs & derivatives
Dacarbazine - pharmacology
Deoxyribonucleic acid
Depletion
DNA
DNA damage
DNA repair
Durability
Enzyme Inhibitors - pharmacology
Female
Genotoxicity
Glioma - genetics
Glioma - metabolism
Humans
Inhibitors
Isocitrate Dehydrogenase - genetics
Metabolic pathways
Metabolism
Metabolites
Methylguanine
Methyltransferase
Mice
Mice, SCID
Mismatch repair
Mutation
NAD
NADPH
Nicotinamide
Nicotinamide phosphoribosyltransferase
Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors
Phosphoribosyltransferase
Piperidines - pharmacology
Poly(ADP-ribose) polymerase
Random Allocation
Stress, Physiological - drug effects
Temozolomide
Toxicity
Xenograft Model Antitumor Assays
Xenografts
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Summary:-mutant gliomas are dependent upon the canonical coenzyme NAD for survival. It is known that PARP activation consumes NAD during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD depletion-mediated cytotoxicity in mutant cancer cells. To investigate the impact of temozolomide on NAD metabolism, patient-derived xenografts and engineered mutant -expressing cell lines were exposed to temozolomide, and , both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD biosynthesis. The acute time period (
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-2263