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Abstract <p><b>Objective:</b> Asiatic acid, a pentacyclic triterpenoid, exhibits promising anticancer properties through the modulation of oncogenic pathways. This study evaluates the drug-likeness, toxicity, network pharmacology, molecular docking, and <i>in vitro</i> antiproliferative effects of asiatic acid in oral carcinoma. <b>Methods:</b> Drug-likeness and toxicity were analyzed using SwissADME and ProTox-II, assessing properties such as bioavailability, physicochemical parameters, and toxicity. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape for 35 common targets identified by intersection analysis of asiatic acid-related and oral carcinoma-related proteins. GO and KEGG pathway enrichment analyses were performed to identify biological processes and signaling pathways. Molecular docking and dynamics simulations assessed the binding affinities and stability of the asiatic acid complex with hub proteins (STAT3, mTOR, PIK3R1). Cytotoxicity, morphological changes, cell migration, proliferation, apoptosis, and modulation of key pathways were evaluated in the oral squamous cell carcinoma (OSCC) SCC-4 cell line using MTT assay, phase-contrast microscopy, Transwell migration assay, EdU assay, flow cytometry, and Western blotting, respectively. <b>Results and Discussion:</b> Asiatic acid adheres to Lipinski’s rule of five, exhibits favorable drug-likeness, demonstrates significant gastrointestinal absorption, is not permeable to the blood-brain barrier, and shows no major toxicity. The PPI analysis identified 35 common targets associated with both asiatic acid and oral cancer, with STAT3, mTOR, and PIK3R1 recognized as key hub genes. GO and KEGG analyses indicated enrichment in pathways including JAK-STAT and HIF-1 signaling. Molecular docking demonstrated substantial binding affinity, particularly with PIK3R1 (Vina score: –10.1 kcal/mol), corroborated by stable molecular dynamics simulations. Asiatic acid decreased SCC-4 cell viability in a dose- and time-dependent manner, with significant effects observed at 50 and 100 µM after 24 and 48 h. Phase-contrast microscopy revealed dose-dependent cellular shrinkage, detachment, and rounding. The EdU assay demonstrated reduced DNA synthesis and cell proliferation, with significant reductions at 50 and 100 µM. Cell migration was inhibited, resulting in a decreased number of migrated cells at these concentrations. Similarly, flow cytometry showed a significant increase in apoptosis at higher concentrations. Western blotting confirmed the downregulation of key phosphorylated signaling proteins <i>p</i>-STAT3, <i>p</i>-mTOR, and PIK3R1, indicating the inhibitory role of asiatic acid on these pathways. <b>Conclusions:</b> Asiatic acid exhibits favorable pharmacological properties and effectively targets key pathways in oral carcinoma, including STAT3, mTOR, and PIK3R1 signaling, while demonstrating potent cytotoxic, antiproliferative, anti-migratory, and pro-apoptotic effects in SCC-4 cells through the inhibition of <i>p</i>-STAT3, <i>p</i>-mTOR, and PIK3R1.</p>

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Network Pharmacology, In Silico Computational Chemistry, and Experimental Evidence of the Antiproliferative Effects of Asiatic Acid in Oral Carcinoma Cells

  • 期刊论文

  • 发表日期：

    2025年2月1日

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  • F. Shi,
  • X. Wu,
  • D. Cai,
  • F. Zhang,
  • Y. Zhang

摘要

Abstract

Objective: Asiatic acid, a pentacyclic triterpenoid, exhibits promising anticancer properties through the modulation of oncogenic pathways. This study evaluates the drug-likeness, toxicity, network pharmacology, molecular docking, and in vitro antiproliferative effects of asiatic acid in oral carcinoma. Methods: Drug-likeness and toxicity were analyzed using SwissADME and ProTox-II, assessing properties such as bioavailability, physicochemical parameters, and toxicity. A protein-protein interaction (PPI) network was constructed via STRING and Cytoscape for 35 common targets identified by intersection analysis of asiatic acid-related and oral carcinoma-related proteins. GO and KEGG pathway enrichment analyses were performed to identify biological processes and signaling pathways. Molecular docking and dynamics simulations assessed the binding affinities and stability of the asiatic acid complex with hub proteins (STAT3, mTOR, PIK3R1). Cytotoxicity, morphological changes, cell migration, proliferation, apoptosis, and modulation of key pathways were evaluated in the oral squamous cell carcinoma (OSCC) SCC-4 cell line using MTT assay, phase-contrast microscopy, Transwell migration assay, EdU assay, flow cytometry, and Western blotting, respectively. Results and Discussion: Asiatic acid adheres to Lipinski’s rule of five, exhibits favorable drug-likeness, demonstrates significant gastrointestinal absorption, is not permeable to the blood-brain barrier, and shows no major toxicity. The PPI analysis identified 35 common targets associated with both asiatic acid and oral cancer, with STAT3, mTOR, and PIK3R1 recognized as key hub genes. GO and KEGG analyses indicated enrichment in pathways including JAK-STAT and HIF-1 signaling. Molecular docking demonstrated substantial binding affinity, particularly with PIK3R1 (Vina score: –10.1 kcal/mol), corroborated by stable molecular dynamics simulations. Asiatic acid decreased SCC-4 cell viability in a dose- and time-dependent manner, with significant effects observed at 50 and 100 µM after 24 and 48 h. Phase-contrast microscopy revealed dose-dependent cellular shrinkage, detachment, and rounding. The EdU assay demonstrated reduced DNA synthesis and cell proliferation, with significant reductions at 50 and 100 µM. Cell migration was inhibited, resulting in a decreased number of migrated cells at these concentrations. Similarly, flow cytometry showed a significant increase in apoptosis at higher concentrations. Western blotting confirmed the downregulation of key phosphorylated signaling proteins p-STAT3, p-mTOR, and PIK3R1, indicating the inhibitory role of asiatic acid on these pathways. Conclusions: Asiatic acid exhibits favorable pharmacological properties and effectively targets key pathways in oral carcinoma, including STAT3, mTOR, and PIK3R1 signaling, while demonstrating potent cytotoxic, antiproliferative, anti-migratory, and pro-apoptotic effects in SCC-4 cells through the inhibition of p-STAT3, p-mTOR, and PIK3R1.