Glioma stem cells (GSCs) exhibit significant resistance to conventional radiotherapy and chemotherapy, contributing to high recurrence rates in gliomas. Addressing this critical clinical need, we developed DMC-GF, a novel GLUT1-based curcumin derivative, to enhance brain specificity and metabolic stability compared to its predecessor DMC-BH. Pharmacokinetic studies in rats demonstrated that DMC-GF achieved an 8.5-fold increase in brain-to-blood concentration ratio two hours post-intravenous administration, markedly superior to the 0.2-fold increase observed with DMC-BH. In vitro assays showed that DMC-GF exerted a more substantial inhibitory effect on GSC proliferation than DMC-BH (p < 0.01), as assessed by Cell Counting Kit-3D and EdU assays. Mechanistic analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway indicated that DMC-GF's anti-GSC activity is associated with disruption of mitochondrial oxidative phosphorylation. Treatment with DMC-GF at a concentration of 4 µM caused a notable decrease in mitochondrial membrane potential and maximal mitochondrial oxygen consumption. Additionally, exposure to 8 µM DMC-GF led to a marked (> 70%) reduction in SLC25A1, a mitochondrial citrate transporter, protein levels (p < 0.01). Overexpression of SLC25A1 attenuated both the decreased proliferation and enhanced apoptosis caused by DMC-GF (p < 0.01). Furthermore, the proteasome inhibitor MG132 (10 µM) and TRIM33, an E3 ubiquitin ligase involved in proteasome-mediated protein degradation, knockdown via shRNA both abrogated the DMC-GF-mediated decrease in SLC25A1 protein levels (p < 0.05). These findings underscore the potential of DMC-GF as an efficacious targeted therapeutic against GSCs, offering enhanced brain specificity and stability, and elucidating its mechanism involving mitochondrial dysfunction and SLC25A1 degradation.
