The dopamine paradox in glioblastoma oncology: methylxanthine therapy against nicotine-driven pathogenesis

Glioblastoma (GBM), a highly aggressive brain tumor, continues to present poor prognoses despite advancements in standard treatments. Emerging evidence identifies neurotransmitter pathways, particularly dopaminergic signaling, as significant modulators of GBM progression. This editorial examines the "dopamine paradox" in GBM, where D2-like receptors (D2/D3/D4) drive pro-tumor effects, while D1-like receptors (D1/D5) mediate tumor suppression. Nicotine, through its activation of nicotinic acetylcholine receptors, exacerbates GBM progression by stimulating dopaminergic pro-survival pathways, particularly via D2/D3 receptors. Conversely, methylxanthines such as caffeine and theophylline demonstrate potential as anti-GBM agents by modulating D1/D5-driven cAMP pathways. These compounds inhibit phosphodiesterases, increasing intracellular cAMP levels, and mimic D1/D5 receptor activation, leading to apoptosis, reduced proliferation, and chemosensitization. This dualistic dopaminergic signaling framework suggests therapeutic opportunities for methylxanthine repurposing to counteract nicotine-driven GBM pathogenesis. This editorial underscores the need for further exploration of dopaminergic modulation in GBM, highlighting the potential of shifting the balance from pro-tumor D2/D3 signaling to antitumor D1/D5 pathways. Understanding this paradox could pave the way for novel, low-toxicity therapeutic strategies to improve GBM outcomes.