Inhibition of MDA‐MB‐231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation‐mediated p21^WAF1/CIP1 expression

Abstract

Apigenin (4',5,7-trihydroxyflavone), a flavonoid commonly found in fruits and vegetables, has anticancer properties in various malignant cancer cells. However, the molecular basis of the anticancer effect remains to be elucidated. In this study, we investigated the cellular mechanisms underlying the induction of cell cycle arrest by apigenin. Our results showed that apigenin at the nonapoptotic induction concentration inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in the MDA-MB-231 breast cancer cell line. Immunoblot analysis indicated that apigenin suppressed the expression of cyclin A, cyclin B, and cyclin-dependent kinase-1 (CDK1), which control the G2-to-M phase transition in the cell cycle. In addition, apigenin upregulated p21 and increased the interaction of p21 with proliferating cell nuclear antigen (PCNA), which inhibits cell cycle progression. Furthermore, apigenin significantly inhibited histone deacetylase (HDAC) activity and induced histone H3 acetylation. The subsequent chromatin immunoprecipitation (ChIP) assay indicated that apigenin increased acetylation of histone H3 in the p21 promoter region, resulting in the increase of p21 transcription. In a tumor xenograft model, apigenin effectively delayed tumor growth. In these apigenin-treated tumors, we also observed reductions in the levels of cyclin A and cyclin B and increases in the levels of p21 and acetylated histone H3. These findings demonstrate for the first time that apigenin can be used in breast cancer prevention and treatment through epigenetic regulation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 434-444, 2017.

Different propolis samples, phenolic content, and breast cancer cell lines: Variable cytotoxicity ranging from ineffective to potent

“…Histone acetylation is a valuable mechanism of epigenetic regulation. Therefore, Tseng et al suggested that apigenin inhibited breast cancer cell growth through the modulation of epigenetic regulation . In the present study, a remarkable cytotoxic effect of apigenin on MCF‐7 was detected.…”

Natural Polyphenols for Prevention and Treatment of Cancer

“…Possible mechanisms included induction of G 2 /M cell cycle arrest and epigenetic alterations. Apigenin inhibited HDACs, which induced acetylation of histone H3 in the p21 WAF1/CIP1 promoter region, leading to enhanced transcription of p21 WAF1/CIP1 [79]. Similar epigenetic effects were also found in prostate cancer.…”

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Also, studies suggest that combining apigenin with other flavones such as genistein inhibited tumor growth by complexing with Cu (II), thereby significantly enhancing the antitumor properties [62]. In triple-negative breast cancer cells, apigenin results in epigenetic changes by inducing histone H3 acetylation, thereby decreasing cyclin A and cyclin B and increasing p21/Waf1/Cip1 levels [63]. A sub-cytotoxic concentration of apigenin inhibits IFN-γ-induced PD-L1 expression in MDA-MB-468 and 4T1 breast cancer cells, associated with reduced phosphorylation of STAT1, transiently at Tyr701 and persistently at Ser727.…”