NAD+ depletion radiosensitizes 2-DG-treated glioma cells by abolishing metabolic adaptation

Two-deoxy-d-glucose (2-DG) mediated glucose restriction (GR) has been applied as a potential therapeutic strategy for tumor clinical treatments. However, increasing evidences have indicated that 2-DG alone is inefficient in killing tumor cells, and the effect of 2-DG on modifying tumor radio-responses also remains controversial. In this study, we found that 2-DG triggered metabolic adaption in U87 glioma cells by up-regulating nicotinamide phosphoribosyltransferase (NAMPT) and cellular NAD+ content, which abolished 2-DG-induced potential radiosensitizing effect in glioma cells. Strikingly, NAD+ depletion evoked notable oxidative stress by NADPH reduction and hence re-radiosensitized 2-DG-treated glioma cells. Furthermore, isocitrate dehydrogenase-1 (IDH1) mutant U87 glioma cells with deficiency in the rate-limiting enzyme of Preiss‐Handler pathway nicotinate phosphoribosyltransferase (Naprt1) revealed notable 2-DG-induced oxidative stress and radiosensitization. Our findings implied that targeting NAD+ could radiosensitize gliomas with GR, and 2-DG administration could be benefit for tumor patients with IDH1 mutation. [Display omitted] •2-DG ameliorates IR-induced oxidative stress through NAD+ augment.•NAMPT inhibition radiosensitizes metabolically adapted glioma cells.•Glucose restriction is promising in radiosensitizing IDH1 mutant tumors.