. In vitro study and in silico reveal Teucrium Polium L. methanolic extract as an apoptosis inducer and a potential Bcl 2 inhibitor for breast cancer
Therapy of breast cancer (BC) overexpressing the pro-survival protein Bcl-2 remains a major clinical challenge. The discovery of natural anticancer drugs with potential as Bcl-2 inhibitors has generated increasing interest. The medicinal plant Teucrium polium L. (TPL) exhibits pharmacological properties, including anticancer activities. This study aimed to assess the antiproliferative and pro-apoptotic effects of TPL extracts on BC cells and to predict the potential of TPL extract-derived metabolites as Bcl-2 inhibitors. Plant extraction was performed using several solvents, and cell viability was determined. The expression of proteins and genes related to apoptosis was evaluated using Western blot, the Proteome Profiler (TM) Human Apoptosis Array Kit, and qPCR, respectively. Caspase-3/7 and mitochondrial permeability transition pore opening (mPTPO) activities were visualized. GC/MS analysis, molecular docking, and in silico modeling were used for metabolite identification, prediction of their molecular interactions with Bcl-2, and their pharmacokinetic profiles. Among extracts, TPL methanolic extract (TPLME) dose-dependently reduced hormone-dependent and triple-negative BC cell viability, while sparing normal mammary epithelial cells. TPLME induced apoptosis by increasing caspase-3/7 activity, activating distinct apoptotic pathways, and modulating BAX, TP53, and BCL-2 gene expression. Differential BCL-2 expression levels in TPLME-treated BC cells were confirmed by variations in mPTPO activity. After TPLME-derived metabolite identification, molecular docking revealed interactions between key metabolites and the active site of Bcl-2. Predictive analysis revealed the safe pharmacokinetic profiles of TPLME-derived metabolites. These findings highlight the promising potential of TPLME-derived metabolites for the development of novel Bcl-2 inhibitors for BC cells, requiring further chemical development and preclinical investigations using in vivo BC models.
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