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<p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptors. This study investigates the anticancer potential and underlying molecular mechanisms of the traditional ayurvedic formulation <i>Kanchanara guggulu</i> in TNBC cells. The cytotoxic, anti-migratory, and membrane integrity-modulating effects of <i>Kanchanara guggulu</i> on MDA-MB-231 cells were assessed using MTT, wound-healing, and Live/Dead assays. Untargeted LC–MS/MS metabolomics identified over 1,019&#xa0;metabolites, of which 237 met drug-likeness and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) criteria. Network pharmacology revealed 50 shared targets with TNBC-associated proteins, highlighting enrichment in PI3K/AKT/mTOR, HIF-1, AGE–RAGE, calcium signaling, and microRNA-related pathways. Molecular docking (LibDock and CDOCKER) identified top bioactive candidates with strong binding affinity towards AKT1, supported by density functional theory (DFT) showing favorable electronic stability. Experimental validation demonstrated significant dose-dependent cytotoxicity (IC₅₀ = 45 µg/mL), inhibition of migration, and increased cell death. Western blot analysis confirmed downregulation of phospho-AKT and mTOR, indicating suppression of PI3K/AKT/mTOR signaling. Overall, TNBC cells showed reduced proliferative and migratory potential upon treatment, suggesting that <i>Kanchanara guggulu</i> extract exerts anticancer effects and provides promising lead compounds for TNBC therapy development.</p>

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Untargeted metabolomics and network pharmacology unveil AKT1 inhibition by Kanchanara Guggulu in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Kadabagere Narayanaswamy Hemavathi,
  • Ravishankar Pervaje,
  • Thottethodi Subramanya Keshava Prasad,
  • Shobha Dagamajalu

摘要

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptors. This study investigates the anticancer potential and underlying molecular mechanisms of the traditional ayurvedic formulation Kanchanara guggulu in TNBC cells. The cytotoxic, anti-migratory, and membrane integrity-modulating effects of Kanchanara guggulu on MDA-MB-231 cells were assessed using MTT, wound-healing, and Live/Dead assays. Untargeted LC–MS/MS metabolomics identified over 1,019 metabolites, of which 237 met drug-likeness and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) criteria. Network pharmacology revealed 50 shared targets with TNBC-associated proteins, highlighting enrichment in PI3K/AKT/mTOR, HIF-1, AGE–RAGE, calcium signaling, and microRNA-related pathways. Molecular docking (LibDock and CDOCKER) identified top bioactive candidates with strong binding affinity towards AKT1, supported by density functional theory (DFT) showing favorable electronic stability. Experimental validation demonstrated significant dose-dependent cytotoxicity (IC₅₀ = 45 µg/mL), inhibition of migration, and increased cell death. Western blot analysis confirmed downregulation of phospho-AKT and mTOR, indicating suppression of PI3K/AKT/mTOR signaling. Overall, TNBC cells showed reduced proliferative and migratory potential upon treatment, suggesting that Kanchanara guggulu extract exerts anticancer effects and provides promising lead compounds for TNBC therapy development.