Onconase induces caspase-independent cell death in chemoresistant neuroblastoma cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Neuroblastoma is a pediatric cancer with variable treatment outcomes.
• Drug resistance, often mediated by P-glycoprotein (P-gp) and p53 mutations, poses a significant therapeutic challenge.
• Onconase, a protein with known biological activity, has potential as an anticancer agent.

Purpose of the Study:

• To evaluate the efficacy of Onconase against chemosensitive and chemoresistant neuroblastoma cell lines.
• To investigate the mechanisms underlying Onconase-induced cell death.
• To assess the in vivo antitumour activity of Onconase.

Main Methods:

• Cell viability assays were performed on various neuroblastoma cell lines.
• Cell cycle analysis and caspase activity assays were used to study cell death mechanisms.
• Transmission electron microscopy was employed to visualize cellular changes.
• In vivo studies utilized neuroblastoma xenografts in animal models.

Main Results:

• Onconase decreased cell viability in both chemosensitive and chemoresistant neuroblastoma cell lines, including those with high P-gp expression or P-gp expression combined with mutated p53.
• Onconase treatment resulted in a G1 phase cell cycle block.
• Caspase-independent cell death was observed, with evidence suggesting Onconase-induced autophagy contributes to this process.
• Onconase demonstrated significant antitumour activity against both drug-sensitive and drug-resistant neuroblastoma xenografts in vivo.

Conclusions:

• Onconase exhibits potent anticancer activity against a range of neuroblastoma models, including those resistant to conventional chemotherapy.
• The drug-induced cell death mechanism involves cell cycle arrest and autophagy.
• Onconase holds promise as a therapeutic agent for neuroblastoma, even in drug-resistant cases.