Unlocking the Anti-Cancer Potential of Silibinin: A Network Pharmacology and Experimental Approach for Colorectal Cancer Treatment
محل انتشار: دومین کنگره بین المللی کنسرژنومیکس
سال انتشار: 1403
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 83
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شناسه ملی سند علمی:
ICGCS02_161
تاریخ نمایه سازی: 17 دی 1403
چکیده مقاله:
Colorectal cancer (CRC) remains a major global health concern, demanding innovative therapeutic strategies. Silibinin, a natural compound derived from Silybum marianum, has shown promise as a potential therapeutic agent for CRC due to its synergistic effects with existing therapies and its potential as a standalone treatment. However, the comprehensive mechanisms underlying silibinin's anti-CRC activity remain elusive. This study aimed to comprehensively investigate the complex mechanisms of action of silibinin in CRC using a multidisciplinary approach combining network pharmacology, bioinformatics analysis, and experimental validation. Methods: Network pharmacology was employed to identify potential silibinin targets and their involvement in CRC-related pathways. Public databases were utilized to extract CRC-related genes and potential silibinin targets. Following the identification of common targets between silibinin and CRC, Gene Ontology (GO) enrichment analysis (BP, CC, and MF) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify significantly enriched pathways associated with silibinin targets in the R programming language. Compound-target-pathway and protein-protein interaction networks were constructed to visualize the complex interactions between silibinin and its targets, allowing for the identification of key targets. Molecular docking analysis was performed to validate the predicted interactions between silibinin and key target proteins. Finally, in vitro experiments were conducted to evaluate the anticancer activity of silibinin on human CRC cell line HT۲۹. Results: Network pharmacology analysis identified ۸۷ targets for silibinin associated with CRC genes, highlighting a significant overlap in their molecular targets. ۱۰۲ potential targets and ۷۹۶۰ genes related to CRC were collected. The ۸۷ common targets were found to be involved in ۱۲۴ signaling pathways, ۲۶۸ BP, ۶۴ MF, and ۴۳ CC. Notably, the most enriched pathways included "endocrine resistance (hsa۰۱۵۲۲)", "cancer pathways (hsa۰۵۲۰۰)", and "PI۳K-Akt signaling pathway (hsa۰۴۱۵۱)". Docking analysis of critical target proteins such as MTOR (-۱۰.۴ kcal/mol), SRC (-۱۰ kcal/mol), PIK۳CD (-۹ kcal/mol), KIT (-۱۱.۶ kcal/mol), and ABCB۱ (-۱۰.۲ kcal/mol) identified affinity between silibinin and these target proteins, suggesting that silibinin's therapeutic effects can be attributed to its ability to bind to and potentially inhibit the activity of these proteins. In vitro cytotoxicity assay demonstrated the inhibitory effect of silibinin on HT۲۹ cell growth with an IC۵۰ value of ۱۵۸.۸۵ micromolar. This experimental validation provides concrete evidence of silibinin's anticancer activity and reinforces the findings from network pharmacology and molecular docking simulations. Conclusion: This comprehensive study, integrating network pharmacology and experimental validation, provides strong evidence for silibinin's potential as a therapeutic agent for CRC. Our findings reveal the multifaceted mechanisms of silibinin's anti-CRC activity and support its potential as a promising therapeutic agent. Silibinin can target multiple pathways and proteins related to cancer development, including the PI۳K/AKT pathway, potentially inhibiting resistance to anticancer drugs and preventing cancer cell migration. The integration of network pharmacology, bioinformatic analysis, and experimental validation provides a strong foundation for further research and clinical translation. This study underscores the importance of multidisciplinary approaches to uncover the complex mechanisms of natural compounds and paves the way for the development of new treatments with increased efficacy and reduced side effects.
کلیدواژه ها:
نویسندگان
Hossein Ebrahimian
Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Seyyed Mobin Rahimian
Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran