Antiproliferative Mechanisms of a Polyphenolic Combination of Kaempferol and Fisetin in Triple-Negative Breast Cancer Cells

Herein, we investigate the combinatorial therapeutic effects of naturally occurring flavonoids kaempferol (K) and fisetin (F) on triple-negative breast cancer (TNBC: MDA-MB-231 cell line). Dose-dependent MTT assay results show that K and F exhibited cytotoxicity in MDA-MB-231 cells at 62 and 75 μM (IC₅₀), respectively, after 24 h. However, combined K + F led to 40% and more than 50% TNBC cell death observed at 10 and 20 μM, respectively, which revealed the synergistic association of both. The combination of K and F was determined to be more effective in inhibiting cell viability than either of the agents alone. The morphological changes associated with significant apoptotic cell death were observed under a fluorescent microscope, strongly supporting the synergistic association between K and F. We also proposed that combining the effects of both polyphenols, as opposed to their individual effects, would increase their in vitro efficacy. Furthermore, we assessed the cell death pathway by the combinational treatment via reactive oxygen species-induced DNA damage and the mitochondrially mediated apoptotic pathway. This study reveals the prominent synergistic role of phytochemicals, which helps in elevating the therapeutic efficacy of dietary nutrients and that anticancer effects may be a result of nutrients that act in concert.