Targeting glioblastoma multiforme with Demethoxycurcumin and its analogues: current evidence and future directions.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with median survival rarely exceeding 15 months under current therapy with surgery, radiotherapy, and temozolomide (TMZ). Resistance mechanisms, tumor heterogeneity, and glioma stem cells (GSCs) remain major obstacles. Curcumin has shown pleiotropic anticancer effects, but its poor bioavailability and limited blood–brain barrier (BBB) penetration restrict clinical utility. Demethoxycurcumin (DMC), a natural curcuminoid analogue, provides greater chemical stability and potent multi-targeted activity. In vitro studies reveal that DMC inhibits phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and nuclear factor kappa-B (NF-κB) signaling, induces mitochondrial apoptosis via reactive oxygen species (ROS) accumulation, and downregulates excision repair cross-complementation group 1 (ERCC1), thereby enhancing chemosensitivity. Importantly, restoration of microRNA-145 (miR-145) synergizes with DMC to suppress SRY-box transcription factor 2 (SOX2) and Wingless/β-catenin (Wnt/β-catenin) signaling in GSCs. Another analogue, dimethoxycurcumin (DiMC, also known as ASC-J9), offers improved metabolic stability and exerts strong pro-oxidant activity. DiMC induces G2/M cell cycle arrest, promotes both apoptosis and autophagy through ROS generation, and has demonstrated radiosensitizing properties in preclinical models. To address solubility and delivery challenges, several synthetic derivatives have been developed. DMC-BH improves aqueous solubility and brain penetration, acting through c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/ERK) hyperactivation in GSCs and PI3K/Akt/mechanistic target of rapamycin (mTOR) inhibition in bulk tumor cells. DMC-GF further enhances brain uptake via glucose transporter 1 (GLUT1) and selectively disrupts mitochondrial oxidative phosphorylation (OXPHOS) by degrading solute carrier family 25 member 1 (SLC25A1), leading to metabolic collapse in GSCs. DMC-TPP targets mitochondria directly, inhibiting thioredoxin reductase (TrxR) and inducing potent caspase-dependent apoptosis. Finally, DMC-HA functions as a hydroxamic acid-based histone deacetylase (HDAC) inhibitor, combining epigenetic modulation with suppression of epithelial–mesenchymal transition (EMT) and signal transducer and activator of transcription 3 (STAT3) signaling. Collectively, these agents exemplify rational drug design to optimize curcuminoids for GBM therapy. Although no clinical trials exist, preclinical data strongly support their potential as adjuncts or alternatives to current regimens.