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

ABSTRACT: IDH1-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 IDH1 cancer cells. To investigate the impact of temozolomide on NAD⁺ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which bl

SUBMITTER: Tateishi K 

PROVIDER: S-EPMC5783559 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature