Antiproliferative Activity of Selenium-Enriched Coumarin Derivatives on the SK-N-SH Neuroblastoma Cell Line: Mechanistic Insights

Abstract

Thirty selenium-containing coumarin derivatives were synthesized and evaluated for inhibitory activity against 17 malignant tumor cell lines. Among these, compound 11i demonstrated the most potent inhibition of neuroblastoma SK-N-SH cells, with an IC₅₀ of 2.5 ± 0.1 μM. Compound 11i notably inhibited SK-N-SH cell proliferation, migration, and invasion. Western blot and immunofluorescence analyses indicated that 11i increased the Bax/Bcl-2 protein expression ratio, promoted Cytochrome C release from mitochondria, and activated caspases 9 and 3, triggering the mitochondria-mediated apoptotic pathway and inducing endogenous tumor cell apoptosis. The compounds localized in the cytoplasm and co-localized with mitochondria, suggesting mitochondrial interaction and dysfunction. Computational docking studies revealed a strong binding affinity of 11i with Bcl-2 and mitochondrial G-quadruplexes. In a subcutaneous neuroblastoma-bearing mouse model, 11i showed notable anti-tumor efficacy with tumor inhibition rates of 79% (10 mg/kg) and 93% (20 mg/kg), exceeding that of cyclophosphamide. This study represents a novel finding on the anti-tumor activity of selenium-containing coumarin derivatives and provides a theoretical basis for developing coumarin-based therapeutics for neuroblastoma.