Network-Guided Identification of Plant-Derived Modulators of Stress-Adaptive Signalling in Neuroblastoma

Area of Science:

• Molecular Biology
• Pharmacology
• Computational Chemistry

Background:

• Neuroblastoma exhibits significant chemotherapy resistance due to adaptable signaling networks.
• Understanding drug mechanisms and identifying novel therapeutic strategies are crucial for treating neuroblastoma.

Purpose of the Study:

• To investigate doxorubicin's effect on adaptive signaling pathways in neuroblastoma cells.
• To explore the potential of plant metabolites in exploiting neuroblastoma's biochemical vulnerabilities.

Main Methods:

• Transcriptomic profiling (RNA sequencing) to analyze pathway alterations post-doxorubicin treatment.
• Protein-protein interaction analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway evaluation.
• Molecular docking and dynamics simulations to predict metabolite-target interactions.
• In vitro Cell Counting Kit-8 (CCK-8) assays to assess anti-neuroblastoma efficacy.

Main Results:

• Doxorubicin disrupted pathways involved in amyloidogenesis, oncogenesis, oxidative stress, and DNA repair.
• Five key network hubs identified: BRAF, GSK3β, PARP1, BACE1, and MAOB.
• Three plant metabolites (Lactol, Amino(1H-indol-2-yl)acetic acid, Quercetin-3-(6″-malonyl-glucoside)) showed significant binding affinity to these hubs.
• Amino(1H-indol-2-yl)acetic acid demonstrated the lowest IC50, indicating potent anti-neuroblastoma activity comparable to doxorubicin.

Conclusions:

• Plant-derived metabolites may effectively target stress-adaptive signaling pathways in neuroblastoma.
• These findings suggest a promising avenue for developing novel, natural-product-based neuroblastoma therapies.
• Experimental validation is necessary to confirm the predicted interactions and therapeutic potential.