Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD⁺ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells.

ABSTRACT: NAD⁺ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD⁺ metabolic pathways. PARPs catalyze oligomerization of NAD⁺ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD⁺ by preventing PAR breakdown

SUBMITTER: Nagashima H 

PROVIDER: S-EPMC7642007 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature