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

Abstract

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.

Kaempferol and Fisetin-Related Signaling Pathways Induce Apoptosis in Head and Neck Cancer Cells

“…Apoptosis-inducing properties in transformed cells are key features of a potential chemopreventive agent [ 36 ]. Numerous reports have shown that fisetin and kaempferol induce cytotoxic effects on human cell lines by arresting the cell cycle and apoptosis, such as: bladder cancer [ 36 ], intestinal cancer [ 27 , 37 ], breast cancer [ 38 , 39 ], gastric cancer [ 40 , 41 ], prostate cancer [ 42 ], pancreatic cancer [ 43 ], ovarian cancer [ 44 ], liver cancer [ 45 ], skin cancer [ 46 ], cervical cancer [ 36 ], lung cancer [ 47 ], brain cancer [ 48 ], osteosarcoma [ 49 ], melanoma [ 50 ], multiple myeloma [ 51 ], leukemia [ 18 , 52 ], endometrial cancer [ 53 ], and head and neck cancers [ 16 ].…”

The role of kaempferol in gynaecological malignancies: progress and perspectives

“…Ackland et al (2005) discovered that quercetin and kaempferol synergistically reduce cell proliferation in the PMC42 human mammary cell line at physiological concentrations between 1 and 10 of 5 ÌM. Afzal et al (2023) reported that the combination of kaempferol and laccasein is more effective in inhibiting the proliferation of TNBC cancer cells (MDA-MB-231) than either substance alone. The co-administration of kaempferol and laccasein resulted in the downregulation of p-Akt protein expression and inhibition of the PI3K/Akt pathway.…”

Targeting colorectal cancer using dietary flavonols

“…Kaempferol in low concentration was very effective when combined with curcumin at 12.5 μM (IC50). This combination of kaempferol and curcumin showed significant antiproliferative activity against colon cancer cells (HCT‐15) and human normal lymphocytes [ 46 , 47 ]. Recent studies in the literature clarified that kaempferol is a promising phytopharmaceutical used in the management of colon cancer via mediating inflammation and signal transduction pathways [ 48 ].…”