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bioRxiv · 10.1101/2025.03.31.646300

Vitronectin binding affinity and cell viability effect of novel mechanotherapy drugs for neuroblastoma

Alaribe, S. C.·Granados-Aparici, S.·Oladipupo, A. R.·Vieco-Marti, I.·Titilayo, B. E.·Allen, G.·Noguera, R.
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Abstract

High-risk neuroblastoma (HR-NB) is an aggressive form of childhood cancer with a five-year survival rate of under 50%, underscoring the need for more efficacious and less toxic treatments. The glycoprotein Vitronectin (VN) has been linked to poor prognosis in patients with HR-NB, and thus inhibitors of its function represent a promising avenue for molecular mechanotherapy. The present study sought to investigate the binding affinity between the somatomedin B (SMB) domain of VN and natural compounds derived from medicinal plants. The therapeutic potential of -amyrin (AMY), lupeol (LUP), and Olax chalcone A (Olax CHA) was tested in combination with an integrin antagonist of VN, cilengitide (CLG), using the SK-N-BE(2) HR-NB cell line as a model. Molecular docking studies indicated a potential for protein-ligand interactions for all selected compounds, of which CLG demonstrated the most favorable binding free energy (kcal/mol), followed by LUP, AMY and Olax CHA. Molecular dynamics simulations demonstrated that the SMB domain of VN initially exhibited flexibility, with alpha carbon-root mean square deviation (RMSD) stabilizing at approximately 1.8-2.1 [A]. While all compounds demonstrated a dose-dependent decrease in SK-N-BE(2) cell viability, CLG exhibited higher IC50 values. Although the combination of AMY and LUP with CLG did not result in enhanced efficacy, Olax CHA exhibited a superior antiproliferative effect with higher IC50 values than AMY and LUP, and additionally showed potential synergism with CLG, suggesting a more effective therapeutic approach. This work provides valuable insights into the potential use of mechanotherapy drugs and natural products to enhance HR-NB treatment that can be expanded in future studies centered on Olax CHA.

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Alaribe, S. C., Granados-Aparici, S., Oladipupo, A. R., Vieco-Marti, I., Titilayo, B. E., Allen, G., Noguera, R.. 2025-04-03. Vitronectin binding affinity and cell viability effect of novel mechanotherapy drugs for neuroblastoma. https://doi.org/10.1101/2025.03.31.646300

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