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.