Quantitative Proteomics Unveils the Synergistic Effects of Combination Drugs on Cytoskeleton Composition and
Pei-Chen Yu1, Yi-Chun Kao2, Hsin-Yi Chang3
1Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan.
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.
Insights
Combining pyrvinium pamoate and sirolimus shows promise for treating neuroblastoma. This drug combination effectively targets neuroblastoma cells, offering a potential new therapy for this aggressive childhood cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Neuroblastoma is an aggressive childhood cancer with limited effective treatments.
- Drug repurposing is a promising strategy for developing novel cancer therapies.
- Identifying effective drug combinations is crucial for improving treatment outcomes.
Purpose of the Study:
- To identify FDA-approved drugs for potential neuroblastoma combination therapy.
- To investigate the synergistic therapeutic effects of pyrvinium pamoate and sirolimus in neuroblastoma.
- To elucidate the molecular mechanisms underlying the efficacy of this combination therapy.
Main Methods:
- Systematic analysis of small-molecule perturbation gene expression data from the LINCS database.
- Colony formation assays and organoid culture to assess therapeutic efficacy.
- Quantitative proteomics using tandem mass tag labeling to identify protein changes.
- Gene set enrichment analysis and DAVID for pathway analysis.
Main Results:
- Pyrvinium pamoate and sirolimus were identified as potential combination therapy candidates.
- The combination therapy demonstrated superior efficacy compared to monotherapy in vitro.
- Combination treatment led to decreased cytoskeleton formation, reduced cell migration, cell cycle arrest, and increased autophagy.
- Proteomic analysis identified 3416 proteins affected by the combination therapy.
Conclusions:
- The combination of pyrvinium pamoate and sirolimus offers a potent therapeutic strategy for neuroblastoma.
- This combination therapy exhibits enhanced efficacy through mechanisms including reduced cell migration and induced autophagy.
- The findings provide a mechanistic basis for advancing this drug combination for neuroblastoma treatment.
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