Anti-cancer agents in medicinal chemistry · 2026
Drug Repositioning of Cardiac Steroids as Potential Agents for the Treatment of Triple‑Negative Breast Cancer.
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Al-Shun Sara A, Youssef Magdy M, Badria Farid A
Аннотация
INTRODUCTION: Triple-Negative Breast Cancer (TNBC) lacks targeted therapies and is mainly treated with chemotherapeutics limited by toxicity and resistance. This study aims to identify and characterize cardiac steroids as potential anti-TNBC leads using phenotypic screening, drug-likeness evaluation, and in silico targetprofiling.
METHODS: A panel of natural products was screened against TNBC MDA-MB-231 cells using MTT assay and compared with conventional chemotherapeutics; selectivity indices were calculated using WI-38 fibroblasts. SwissADME was used to predict physiochemical and pharmacokinetic properties. Putative targets of the top hit were predicted, intersected with breast-cancer-associated genes, and subjected to Protein-Protein Interaction (PPI) and enrichment analyses to identify hub targets. VEGFA was selected for Molecular Docking and (MD) molecular dynamics simulations with digitoxigenin.
RESULTS: The cardiac steroids digitoxin, digitoxigenin, and ouabain exhibited the greatest potency with lownanomolar IC₂⁽ values that markedly surpassed those of cisplatin, doxorubicin, and sorafenib. Digitoxigenin displayed the most favorable selectivity (SI = 4.2). SwissADME favored digitoxigenin over digitoxin with no Lipinski violations. Target-profiling highlighted angiogenesis- and signaling-related hub proteins, including VEGFA. Molecular docking and MD simulations suggested a stable digitoxigenin-VEGFA complex.
DISCUSSION: These data support digitoxigenin as a prioritized cardiac steroid scaffold that combines potent in vitro cytotoxicity with improved selectivity and a more favorable drug-likeness profile than digitoxin, while the in silico analyses provide a mechanistic hypothesis centered on angiogenesis and survival signaling.
CONCLUSION: Digitoxigenin emerges as a promising anti-TNBC lead. The in silico analyses generate mechanistic hypotheses that warrant future biochemical validation and in vivo efficacy and cardiotoxicity studies in TNBC models.
METHODS: A panel of natural products was screened against TNBC MDA-MB-231 cells using MTT assay and compared with conventional chemotherapeutics; selectivity indices were calculated using WI-38 fibroblasts. SwissADME was used to predict physiochemical and pharmacokinetic properties. Putative targets of the top hit were predicted, intersected with breast-cancer-associated genes, and subjected to Protein-Protein Interaction (PPI) and enrichment analyses to identify hub targets. VEGFA was selected for Molecular Docking and (MD) molecular dynamics simulations with digitoxigenin.
RESULTS: The cardiac steroids digitoxin, digitoxigenin, and ouabain exhibited the greatest potency with lownanomolar IC₂⁽ values that markedly surpassed those of cisplatin, doxorubicin, and sorafenib. Digitoxigenin displayed the most favorable selectivity (SI = 4.2). SwissADME favored digitoxigenin over digitoxin with no Lipinski violations. Target-profiling highlighted angiogenesis- and signaling-related hub proteins, including VEGFA. Molecular docking and MD simulations suggested a stable digitoxigenin-VEGFA complex.
DISCUSSION: These data support digitoxigenin as a prioritized cardiac steroid scaffold that combines potent in vitro cytotoxicity with improved selectivity and a more favorable drug-likeness profile than digitoxin, while the in silico analyses provide a mechanistic hypothesis centered on angiogenesis and survival signaling.
CONCLUSION: Digitoxigenin emerges as a promising anti-TNBC lead. The in silico analyses generate mechanistic hypotheses that warrant future biochemical validation and in vivo efficacy and cardiotoxicity studies in TNBC models.