α-Viniferin Induces Intrinsic Apoptosis in Triple-Negative Breast Cancer Cells and Synergizes With SB203580 Independently of p38 Mitogen-Activated Protein Kinase

초록

Purpose: Triple-negative breast cancer (TNBC) is recognized as the most aggressive subtype of breast cancer. Due to the absence of established molecular targets, treatment options remain limited. In this study, we investigated the anticancer effects of alpha alpha-viniferin in TNBC cells. Methods: The impact of alpha alpha-viniferin on cell viability was evaluated across several breast cancer cell lines representing different molecular subtypes, as well as in human dermal fibroblasts, using MTT assays. Apoptotic cell death, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels were assessed through flow cytometry. The involvement of signaling pathways was investigated via western blotting and small interfering RNA (siRNA)-mediated knockdown of p38 alpha and p38(3. Results: Our findings revealed that alpha alpha-viniferin induced apoptotic cell death in a time-and dose-dependent manner more effectively in TNBC cells than in other breast cancer subtypes. alpha alpha-Viniferin triggered intrinsic apoptotic cell death in TNBC cells by downregulating antiapoptotic Bcl-2 family proteins, disrupting MMP, and cleaving poly(ADP-ribose) polymerase and caspase-3, which is accompanied by increased intracellular ROS levels. Notably, SB203580, a selective p38 inhibitor, synergistically enhanced alpha alpha-viniferin-induced cytotoxicity. However, this synergistic effect was independent of p38 mitogen-activated protein kinase (MAPK) signaling, as siRNA-mediated knockdown of p38 alpha and p38(3 did not replicate the observed synergistic cell death in TNBC cells. Conclusion: Collectively, these findings indicate that alpha alpha-viniferin induces apoptotic cell death in TNBC cells and that SB203580 enhances this cytotoxic effect through a mechanism independent of p38 MAPK signaling, suggesting a potential combination strategy for the treatment of TNBC.

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