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Updated: Jun 4, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Drug repositioning in castration-resistant prostate cancer using systems biology and computational drug design
Javad Rafiee1, Khadijeh Jamialahmadi2, Mohammad Javad Bazyari3
1Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Background And Objective:
Castration-resistant prostate cancer (CRPC) is caused by resistance to androgen deprivation treatment and leads to the death of patients and there is almost no chance of survival. Therefore, finding a cure to overcome CRPC is challenging and important, but discovering a new drug is very time-consuming and expensive. To overcome these problems, we used Drug repositioning (drug repurposing) strategy in this study.
Methods:
Gene expression data of CRPC and primary prostate samples were extracted from the GEO database to identify DEGs. Pathway enrichment was performed to find the role of DEGs in signaling pathways. To identify hub proteins, the PPI network was reconstructed and analyzed. drug candidates were identified and to select the most effective drug, molecular docking analysis, and molecular dynamics simulation were performed. Then MTT and qRT-PCR tests were performed to check the effectiveness of the selected drug.
Results:
A total of 152 upregulated DEGs and 343 downregulated DEGs were identified, and after PPI network analysis, IKBKB, SNAP23, MYC, and NOTCH1 genes were introduced as hubs. drug candidates for IKBKB were identified and by examining the results of docking screening and molecular dynamics, sulfasalazine was selected as the most effective drug. Laboratory analyses proved the effectiveness of this drug and a decrease in the expression of all target genes was observed.
Conclusion:
In this study, IKBKB key protein were identified in CRPC, and sulfasalazine was selected as a suitable candidate for drug repositioning and its effectiveness was confirmed through tests.
Insights
This study repurposed sulfasalazine to treat castration-resistant prostate cancer (CRPC). The drug effectively targeted key IKBKB protein, showing promise for CRPC patients with limited survival options.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Castration-resistant prostate cancer (CRPC) is a lethal disease resistant to standard androgen deprivation therapy.
- Developing novel CRPC treatments is crucial but faces challenges of time and cost.
- Drug repositioning offers a faster, more economical approach to identify new therapeutic agents.
Purpose of the Study:
- To identify potential drug candidates for CRPC using a drug repositioning strategy.
- To investigate the efficacy of identified candidates through computational and experimental methods.
Main Methods:
- Differential gene expression analysis of CRPC and primary prostate samples.
- Pathway enrichment and protein-protein interaction (PPI) network analysis to identify key genes and hub proteins.
- Molecular docking and dynamics simulations to screen and select drug candidates.
- In vitro validation using MTT and qRT-PCR assays.
Main Results:
- Identified 152 upregulated and 343 downregulated differentially expressed genes (DEGs).
- IKBKB, SNAP23, MYC, and NOTCH1 were identified as key hub genes.
- Sulfasalazine was computationally selected as the most effective drug candidate targeting IKBKB.
- Laboratory tests confirmed sulfasalazine's efficacy in CRPC, showing decreased target gene expression.
Conclusions:
- IKBKB is a key protein target in CRPC.
- Sulfasalazine is a promising candidate for drug repositioning in CRPC treatment.
- Experimental validation supports sulfasalazine's therapeutic potential for CRPC.
