Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD⁺ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase.

ABSTRACT: Glioblastoma multiforme (GBM) is an incurable brain cancer with an average survival of approximately 15 months. Temozolomide (TMZ) is a DNA alkylating agent for the treatment of GBM. However, at least 50% of the patients treated with TMZ show poor response, primarily due to elevated expression of the repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) or due to defects in the mismatch repair (MMR) pathway. These resistance mechanisms are either somatic or arise in response to treatment, highlighting the need to uncover treatments to overcome resistance. We found that administration of the NAD⁺ precursor dihydronicotinamide riboside (NRH) to raise cellular NAD⁺ levels combined with PARG inhibition (PARGi) triggers hyperaccumulation of poly(ADP-ribos

SUBMITTER: Li J 

PROVIDER: S-EPMC9331395 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature