10.3390/polym8030084

Vollständiger Abstract

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<b>Background/Objectives</b>: Colorectal cancer (CRC) remains a leading cause of cancer-associated mortality worldwide. The current therapeutic interventions are heavily constrained by the development of resistance and severe systemic toxicity. To address these challenges, this study integrated a multi-disciplinary framework involving high-throughput in silico screening followed by in vitro experimental validation to identify novel genetic targets of CRC and evaluate the efficacy of FDA-approved drugs. The primary objective was to identify safe and selective therapeutic agents capable of modulating their effect. <b>Methods</b>: The methodology employed a systematic screening of recent large-scale Genome-Wide Association Studies (GWASs) to pinpoint novel targets, followed by in silico pathogenicity prediction, homology modelling and high-throughput virtual screening of over 1615 FDA-approved drugs. The prioritized candidates were validated in vitro using MTT cytotoxicity assays and differential gene expression analysis across CRC cell lines (HCT116 and HT29) and a non-tumorigenic control, Human embryonic kidney cell line HEK293. <b>Results</b>: In silico analysis identified <i>CLUH</i>, <i>CLSTN3</i> and <i>SLC11A2</i> as novel potential targets. Based on in silico predicted deleterious mutations and subsequent molecular docking-based virtual screening, Telmisartan, Dutasteride and Venetoclax were prioritized. This prioritization was supported by their high binding affinity and dose-dependent cytotoxicity in MTT assays; thus, suggesting their repurposing potential for CRC treatment. Telmisartan exhibited a superior therapeutic profile not only in terms of the statistically significant cytotoxicity (<i>p</i> < 0.01), but also its selective effect on HCT116 and HT29 when compared to high safety profile in HEK293. This was further validated when Telmisartan selectively downregulated <i>CLUH</i> and <i>SLC11A2</i> in CRC cell lines, HCT116 and HT29 while maintaining expression levels in the non-cancerous HEK293 cell line remained significantly unaffected. Furthermore, a 100 ns molecular dynamics simulation confirmed the stable binding conformation and structural reliability of the SLC11A2 (Trp179Ser)-Telmisartan complex. <b>Conclucions</b>: Our findings conclude that Telmisartan is a promising candidate for drug repurposing for CRC treatment and capable of modulating selected novel biomarkers <i>CLUH</i> and <i>SLC11A2</i>. However, further multi-omics-based confirmatory studies and pre-clinical validation studies are needed in the future to confirm the long-term efficacy of this repositioning strategy.

Abstract: PubMed · Datensatz