Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway

Abstract

BackgroundFlavones found in plants display various biological activities, including anti-allergic, anti-viral, anti-inflammatory, anti-oxidation, and anti-tumor effects. In this study, we investigated the anti-tumor effects of flavone, apigenin and luteolin on human breast cancer cells.MethodsThe anti-cancer activity of flavone, apigenin and luteolin was investigated using the MTS assay. Apoptosis was analyzed by Hoechst 33342 staining, flow cytometry and western blot. Cell migration was determined using the culture inserts and xCELLigence real-time cell analyzer instrument equipped with a CIM-plate 16. Real-time quantitative PCR and western blot were used to determine the signaling pathway elicited by flavone, apigenin and luteolin.ResultsFlavone, apigenin and luteolin showed potent inhibitory effects on the proliferation of Hs578T, MDA-MB-231 and MCF-7 breast cancer cells in a concentration and time-dependent manner. The ability of flavone, apigenin and luteolin to inhibit the growth of breast cancer cells through apoptosis was confirmed by Hoechst33342 staining and the induction of sub-G1 phase of the cell cycle. Flavone, apigenin and luteolin induced forkhead box O3 (FOXO3a) expression by inhibiting Phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB)/Akt. This subsequently elevated the expression of FOXO3a target genes, including the Cyclin-dependent kinase inhibitors p21Cip1 (p21) and p27kip1 (p27), which increased the levels of activated poly(ADP) polymerase (PARP) and cytochrome c.ConclusionTaken together, these data demonstrated that flavone, apigenin and luteolin induced cell cycle arrest and apoptosis in breast cancer cells through inhibiting PI3K/Akt activation and increasing FOXO3a activation, which suggest that flavone, apigenin and luteolin will be the potential leads for the preventing and treating of breast cancer.

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Apigenin exerts its toxic effects on breast cancer cells while causing minimal damage to healthy cells, thereby indicating its selectivity in inhibiting tumor possession [45]. In triple-negative breast cancer cells, apigenin induces apoptosis by inhibiting the PI3K/Akt pathway thereby increasing FOXO3a expression that may attenuate cell migration and invasion-inducing apoptosis [46]. …”

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

“…1B and C). Apoptosis rates are 27 and 37% for the cells treated with flavone compared to 13 and 25% for control group respectively in MDA-MB-231 and MCF-7 cells (24). Apoptosis is increased about 2.4-to 3.1-fold induced by flavonoid for 36 h in LNCaP cells (33).…”

“…Flavone (2-phenyl-4H-1-benzopyran-4-one) is the core structure of flavonoids, which induces apoptosis potent in human colon carcinoma cells (22,23). Flavone inhibits PI3K/AKT and increases FoxO3a activation to induce apoptosis in breast cancer cells (24).…”

Ancient oncogenesis, infection and human evolution

“…The relative contribution of intrinsic (inheritable genetic) and extrinsic (environmental) risk factors in cancer development has been the subject of extensive scientific discussion (Lin et al., ; Luzzatto & Pandolfi, ; Ngeow & Eng, ; Pimenoff et al., ; Plummer et al., ; Tomasetti & Vogelstein, ; Wu, Lu, Zhou, Chen, & Xu, ; Wu, Powers, Zhu, & Hannun, ). Carcinogenesis or oncogenesis entails the process whereby normal cells are transformed into cancer cells.…”

“…For breast cancer, a leading cause of cancer‐related death in women, the most important genes implicated are BRCA1 and BRCA2. These mutations are however only responsible for 10%–20% of cancer cases in patients with early‐onset or a family history of breast cancer (Lin et al., ). Mutations in the TP53 gene are one of the most frequent genetic alterations in human cancers (Olivier, Hollstein, & Hainaut, ).…”