A native dairy-derived Streptococcus thermophilus potentiates docetaxel efficacy by modulating apoptotic and PI3K/AKT/mTOR signaling pathways in MCF-7 breast cancer cells

Abstract

Docetaxel (DTX) is a widely used chemotherapeutic agent for breast cancer; however, its clinical application is limited by dose-dependent toxicity and chemoresistance. This study investigated the chemosensitizing potential of a native dairy-derived S. thermophilus strain in combination with DTX against MCF-7 breast cancer cells. Sixty traditional fermented dairy samples collected from Fars Province, Iran, were screened for lactic acid bacteria. The selected isolate was identified by 16 S rRNA gene sequencing as S. thermophilus Ab.341 TH and deposited in GenBank under accession number PX307500. Cytotoxicity was evaluated by MTT assay in MCF-7 breast cancer cells and MCF-10 A non-tumorigenic mammary epithelial cells. Apoptosis-related gene expression was analyzed by quantitative real-time PCR, and apoptotic cell death was evaluated using Annexin V-FITC/PI flow cytometry. S. thermophilus Ab.341 TH reduced MCF-7 cell viability in a concentration-dependent manner while exhibiting limited effects on MCF-10 A cell viability under the tested conditions. DTX alone showed an IC₅₀ of approximately 30 µg/mL, whereas combination treatment with S. thermophilus (OD₆₀₀ = 0.85) reduced the effective DTX concentration to 150 ng/mL, representing an approximately 200-fold reduction in the concentration required to achieve comparable cytotoxic effects in vitro. Combination treatment increased the expression of apoptosis-associated genes, including Caspase-3, Caspase-8, Caspase-9, BAX, Fas, PTEN, P53, and P21, while decreasing the expression of survival-related genes including AKT, mTOR, and BCL-2. Increased IκB expression suggested modulation of NF-κB-associated signaling responses. Flow cytometry confirmed enhanced apoptotic cell death, with 23.52% early and 20.56% late apoptotic populations and minimal necrosis. S. thermophilus Ab.341 TH enhances MCF-7 breast cancer cell sensitivity to docetaxel under in vitro conditions through modulation of apoptosis-associated and survival-related gene expression patterns. These findings support the potential application of this native probiotic strain as a biological chemosensitizer; however, further mechanistic validation, in vivo studies, and pharmacological synergy analyses are required to determine its translational relevance. Illustrating the proposed chemosensitizing anticancer mechanism of the dairy-derived probiotic S. thermophilus Ab.341 TH in combination with docetaxel (DTX) against MCF-7 breast cancer cells. S. thermophilus enhances the antitumor activity of DTX by activating both the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways through upregulation of Caspase-3, Caspase-8, Caspase-9, BAX, PTEN, P53, P21 , and Fas, while suppressing the PI3K/AKT/mTOR survival signaling axis and reducing BCL-2 expression. The combination treatment markedly decreases the effective in vitro concentration of DTX (approximately 200-fold) while enhancing apoptotic cell death and docetaxel responsiveness in breast cancer cells, suggesting the potential of S. thermophilus Ab.341 TH as a probiotic-assisted chemosensitizing strategy.