Quantitative Proteomics Unveils the Synergistic Effects of Combination Drugs on Cytoskeleton Composition and Autophagy-Mediated Cell Death in Neuroblastoma
Journal
Journal of Proteome Research
Journal Volume
24
Journal Issue
7
Start Page
3578
End Page
3596
ISSN
1535-3893
1535-3907
Date Issued
2025-06-17
Author(s)
Abstract
Neuroblastoma, a prevalent and aggressive childhood cancer, lacks effective treatments. Recent research highlights the repurposing of existing drugs as a strategy for breakthroughs in combating this disease. We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), identifying pyrvinium pamoate and sirolimus, two FDA-approved drugs, as potential candidates for neuroblastoma combination therapy. Colony formation assays and organoid culture confirmed that the therapeutic effect of combining these two drugs exceeded that of either drug alone. The mRNA expression levels of several genes predicted by LINCS also decreased. To comprehensively understand the mechanism behind superior efficacy of the combination therapy compared to monotherapy, we performed quantitative proteomics with tandem mass tag labeling and identified 3416 proteins from 20,623 peptides. Gene set enrichment analysis and Database for Annotation, Visualization, and Integrated Discovery revealed that combination therapy significantly decreased cytoskeleton formation compared with monotherapy, reflecting dramatic reduction in cell migration. Additionally, the research indicated that cell cycle arrest occurred under combination therapy. Furthermore, we confirmed that the extent of autophagy significantly increased after the combination treatment. In summary, this study elucidates the mechanisms and therapeutic potential of combining sirolimus and pyrvinium pamoate for treating neuroblastoma, offering new advancements for this challenging disease.
Subjects
combination therapy
neuroblastoma
pyrvinium pamoate
sirolimus
tandem mass tag
SDGs
Publisher
American Chemical Society (ACS)
Type
journal article