Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning
Artikel i vetenskaplig tidskrift, 2019

Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment. Methods: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions. Findings: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line. Interpretation: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

Genome-scale metabolic models

Drug repositioning

Drug repurposing

Prostate cancer

Approved drugs

Författare

Beste Turanli

Marmara Universitesi

Kungliga Tekniska Högskolan (KTH)

İstanbul Medeniyet Üniversitesi

C. Zhang

Kungliga Tekniska Högskolan (KTH)

Woonghee Kim

Kungliga Tekniska Högskolan (KTH)

Rui Benfeitas

Kungliga Tekniska Högskolan (KTH)

Mathias Uhlen

Kungliga Tekniska Högskolan (KTH)

Kazim Y. Arga

Marmara Universitesi

Adil Mardinoglu

King's College London

Chalmers, Biologi och bioteknik, Systembiologi

Kungliga Tekniska Högskolan (KTH)

EBioMedicine

2352-3964 (eISSN)

Ämneskategorier

Farmaceutisk vetenskap

Bioinformatik och systembiologi

Cancer och onkologi

DOI

10.1016/j.ebiom.2019.03.009

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Senast uppdaterat

2019-04-10