Silymarin'in WNT/β-katenin yolağı aracılığıyla hepatotoksisite ötesinde terapötik yeniden kullanım potansiyelinin keşfi

Year 2023, Volume: 48 Issue: 4, 1299 - 1309, 29.12.2023

Sümeyra Gültekin

https://doi.org/10.17826/cumj.1366590

Abstract

Amaç: Bu çalışmada, silymarinin hepatosellüler karsinom (HCC) için bir ilaç olma potansiyeli in situ olarak değerlendirilmiştir.
Gereç ve Yöntem: Çalışmada SwissADME, silymarinin farmakokinetik ve ilaç benzeri özelliklerini değerlendirmek için kullanılmıştır. Moleküler docking, silymarinin WNT/β-katenin yolağı ile ilişkili olan ve HCC'de bu yolakla ilişkilendirilen moleküler bileşiklerle etkileşimini modellemek için gerçekleştirilmiştir. Hedef proteinler (AFP, PIK3CA, β-katenin, PTEN, AAT, AXIN1, GSTM1, GSK3B, PI3K3CA, GSTT1, CCND1, albumin, p53, MET, CTNNB1 ve APC) SwissTargetPrediction veritabanından elde edilmiştir. Protein-protein etkileşimleri STRING ve Cytoscape veritabanlarından alınmıştır. PASS platformu, potansiyel biyoaktivite özelliklerini tahmin etmek için kullanılmıştır.
Bulgular: Silymarin en iyi bağlanmayı -11,7 Kcal/mol değeriyle APC proteiniyle göstermiştir. Araştırılan proteinler arasında AXIN1 en az bağlanmayı gösterse de, -7,4 Kcal/mol değeri iyi bir bağlanma afinitesi olarak kabul edilebilir.
Sonuç: Bu çalışmada silymarinin WNT/β-katenin yolağının aşırı aktivasyonunu inhibe etme ve hepatoprotektif özelliklerinin ötesinde HCC için potansiyel bir ilaç adayı olma potansiyeli tanımlanmıştır. Bununla birlikte, silymarinin etkinliğini ve güvenliğini doğrulamak için WNT/β-katenin yolağını hedef alan daha fazla preklinik ve klinik araştırmaya ihtiyaç vardır.

Keywords

İlaç yeniden kullanımı, moleküler docking, silymarin, WNT/β-katenin yolağı

Exploring the drug repurposing potential of silymarin beyond hepatotoxicity treatment through WNT/β-catenin signaling pathway

Abstract

Purpose: In this study, the potential of silymarin as a drug for hepatocellular carcinoma (HCC) was evaluated in situ.
Materials and Methods: The SwissADME tool was utilized to assess the pharmacokinetic and drug-like properties of silymarin. Molecular docking was performed to model the interaction of silymarin with molecular compounds known to play a role in the WNT/β-catenin pathway and associated with this pathway in HCC. Target proteins (AFP, PIK3CA, β-catenin, PTEN, AAT, AXIN1, GSTM1, GSK3B, PI3K3CA, GSTT1, CCND1, albumin, p53, MET, CTNNB1, and APC) were obtained from the SwissTargetPrediction database. Protein-protein interactions were obtained from the STRING and Cytoscape databases. The PASS platform was used to predict potential bioactivity properties.
Results: The study data revealed that silymarin exhibited the highest binding affinity to the APC protein, with a value of -11.7 Kcal/mol. Although AXIN1 showed the least binding among the studied proteins, with a value of -7.4 Kcal/mol, this can still be considered a good binding affinity.
Conclusion: This study demonstrated the potential of silymarin to inhibit the overactivation of the WNT/β-catenin pathway and identified silymarin as a potential drug candidate for HCC, beyond its hepatoprotective properties. However, further preclinical and clinical studies targeting the WNT/β-catenin pathway are required to confirm the effectiveness and safety of silymarin.

Keywords

Drug repurposing, molecular docking, silymarin, WNT/β-catenin pathway

References

• Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18:41-58.
• Kulkarni VS, Alagarsamy V, Solomon VR, Jose PA, Murugesan S. Drug repurposing: an effective tool in modern drug discovery. Russ J Bioorg Chem. 2023;49:157-66.
• Akhtar MN, Saeed R, Saeed F, Asghar A, Ghani S, Ateeq H et al. Silymarin: a review on paving the way towards promising pharmacological agent. Int J Food Prop. 2023;26:2256-72.
• Singh M, Kadhim MM, Turki Jalil A, Oudah SK, Aminov Z, Alsaikhan F et al. A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity. Cancer Cell Int. 2023;23:88.
• Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24:1423-32.
• Aldayel MF. Potential antibacterial and antioxidant inhibitory activities of Silybum marianum mediated biosynthesised He-Ne laser. Saudi J Biol Sci. 2023;30:103795.
• Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants. 2015;4:204-247.
• Koltai T, Fliegel L. Role of silymarin in cancer treatment: facts, hypotheses, and questions. J Evid Based Integr Med. 2022;27:2515690X211068826.
• Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301-14.
• Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022;132:e154515.
• Long J, Wang A, Bai Y, Lin J, Yang X, Wang D et al. Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. EBioMedicine. 2019;42:363-74.
• Colnot S. Deciphering the molecular mechanisms underlying hepatocellular carcinoma. World J Gastroenterol. 2011;17:4852-56.
• Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3.
• Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022;132:e154515.
• Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10:101.
• Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461-73.
• Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010;35:161-8.
• Fu X, Yang Y, Zhang D. Molecular mechanism of albumin in suppressing invasion and metastasis of hepatocellular carcinoma. Liver Int. 2022;42:696-709.
• Chanhom N, Udomsinprasert W, Chaikledkaew U, Mahasirimongkol S, Wattanapokayakit S, Jittikoon J. GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug-induced liver injury. Biomed Rep. 2020;12:153-62.
• Wang H, Rao B, Lou J, Li J, Liu Z, Li A et al. The function of the HGF/c-Met axis in hepatocellular carcinoma. Front Cell Dev Biol. 2020;8:55