Vinorelbine- Autophagy Agent Combinations Induce Synergistic Cytotoxicity in SH-SY5Y Neuroblastoma Cells

Objective: To investigate whether pharmacological agents associated with autophagy induction or inhibition modulate vinorelbine-induced cytotoxic responses in SH-SY5Y neuroblastoma cells.Methods: SH-SY5Y neuroblastoma cells were treated with vinorelbine, lithium chloride (LiCl), medroxyprogesterone acetate (MPA), or clomipramine, either individually or in combination. Cell viability was assessed using the Trypan Blue exclusion assay in a dose- and time-dependent manner. Treatment-induced ultrastructural alterations were examined by transmission electron microscopy after 96 hours.Results: All agents reduced cell viability in a dose- and time-dependent manner. LiCl and clomipramine produced rapid loss of viability, whereas vinorelbine and MPA caused more gradual reductions. Combination treatments, particularly vinorelbine combined with LiCl or clomipramine, resulted in markedly enhanced cytotoxic effects, reducing cell viability to below 20% at 96 hours. Ultrastructural analysis revealed distinct stress-associated morphologies: vinorelbine induced mitotic stress accompanied by secondary autophagic vacuole formation; LiCl caused extensive cytoplasmic vacuolization consistent with enhanced autophagy-associated stress; clomipramine led to pronounced vacuolation and cytoplasmic disorganization; and MPA induced mixed autophagy- and apoptosis-associated features. Combination treatments further intensified these ultrastructural alterations. Although ultrastructural data were not available for the vinorelbine plus MPA group, viability data and single-agent profiles suggest overlapping cytostatic and autophagy-associated stress responses.Conclusion: These findings indicate that agents associated with autophagy induction or inhibition can substantially influence vinorelbine-induced cytotoxic responses in SH-SY5Y neuroblastoma cells. Modulation of autophagy-related stress pathways may represent a rational strategy to enhance the cytotoxic efficacy of microtubule-disrupting agents in neuroblastoma models.