Functional network analysis reveals potential repurposing of β-blocker atenolol for pancreatic cancer therapy

Abstract

Background

The survival rate of patients with pancreatic cancer is low; therefore, continuous discovery and development of novel pancreatic cancer drugs are required. Functional network analysis is an integrated bioinformatics approach based on gene, target, and disease networks interaction, and it is extensively used in drug discovery and development.

Objective

This study aimed to identify if atenolol, a selective adrenergic inhibitor, can be repurposed for the treatment of pancreatic cancer using functional network analysis.

Methods

Direct target proteins (DTPs) and indirect target proteins (ITPs) were obtained from STITCH and STRING databases, respectively. Atenolol-mediated proteins (AMPs) were collected from DTPs and ITPs and further analyzed for gene ontology, KEGG pathway enrichment, genetic alterations, overall survival, and molecular docking.

Results

We obtained 176 AMPs that consisted of 10 DTPs and 166 ITPs. Among the AMPs involved in the pancreatic cancer pathways, several AMPs such as MAPK1, RELA, MAPK8, STAT1, and STAT3 were identified. Genetic alterations in seven AMPs were identified in 0.9%–16% of patients. Patients with high mRNA levels of MAPK1, RELA, STAT3, GNB1, and MMP9 had significantly worse overall survival rates compared with patients with low expression. Molecular docking studies showed that RELA and MMP9 are potential target candidates of atenolol in the treatment of patients with pancreatic cancer.

Conclusion

In conclusion, atenolol can potentially be repurposed to target pancreatic cancer cells by modulating MMP9 and NF-κB signaling. The results of this study need to be further validated in vitro and in vivo.

Graphical abstract

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Data availability

All data generated or analysed during this study are included in the Additional Files of this article.

Abbreviations

ADRB1:

β-Adrenergic 1 Receptor

ADRB2:

β-Adrenergic 2 Receptor

AMPs:

Atenolol-mediated proteins

DAVID:

Database for Annotation, Visualization and Integrated Discovery

DTPs:

Direct target proteins

GO:

Gene Ontology

ITPs:

Indirect target proteins

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MMP:

Matrix metalloproteinase

PPI:

Protein–Protein Interaction

SNP:

Single-Nucleotide Polymorphism

STAT3:

Signal Transducer and Activator of Transcription 3

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Acknowledgments

The authors thank Badan Penerbit dan Publikasi Universitas Gadjah Mada for their assistance in writing.

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This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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AH—conception and design of the study, acquisition, analysis and interpretation of data, drafting and revising the article, HP and RYU—acquisition and analysis of data, drafting the article. All authors had final approval of the submitted manuscript.

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Correspondence to Adam Hermawan.

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Hermawan, A., Putri, H. & Utomo, R.Y. Functional network analysis reveals potential repurposing of β-blocker atenolol for pancreatic cancer therapy. DARU J Pharm Sci 28, 685–699 (2020). https://doi.org/10.1007/s40199-020-00375-4

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Keywords

  • Functional network
  • Atenolol
  • Drug repurposing
  • Pancreatic cancer