Coupling DNA intercalation with redox catalysis: selective killing mechanism of glioblastoma by daidzin

Glioblastoma (GBM) is recognized as one of the most treatment-resistant malignancies, owing to its reinforced DNA repair systems and limited drug accessibility across the blood-brain barrier. This study, identifies, daidzin (DZN), a naturally derived isoflavone, as a potent redox-active DNA intercalator that intrinsically combines physical intercalation with chemical reactivity to breach this resistance. Unlike traditional intercalators, DZN autonomously triggers destabilization of DNA helices by inducing torsional strain, thereby producing convergent strand and base lesions through photo-independent redox pathways involving deoxyribose cleavage and C8 guanine oxidation. Additionally, DZN demonstrates pronounced glioma-specific cytotoxicity by initiating 1O2-driven oxo-cation formation and concomitant H2O2 production. This redox burst results in DNA strand scission activating robust DDR signaling and oxidative base lesions, which cripple tumor survival. Enhanced membrane fluidity in glioma cells likely facilitates superior DZN permeability, intracellular accumulation, thereby allowing DZN to initiate this robust DNA damage responses, culminating in G1 arrest and apoptosis in GBM cells while sparing normal glia. In vivo, DZN markedly suppresses tumor growth and surpasses temozolomide efficacy, current clinical option for GBM treatment. This work, thus, establishes a previously unrecognized paradigm of DNA intercalation-driven redox chemistry, presenting DZN as a promising therapeutic capable of exploiting the genomic frailties to overcome therapeutic resistance in glioma.