Cell-Cycle Arrest at G2/M and Growth Inhibition by Apigenin in Human Colon Carcinoma Cell Lines

Abstract

Apigenin, a common dietary flavonoid, has been shown to induce cell cycle arrest in both epidermal and fibroblast cells and inhibit skin tumorigenesis in murine models. The present study assessed the influence of apigenin on cell growth and the cell cycle in the human colon carcinoma cell lines SW480, HT‐29, and Caco‐2. Treatment of each cell line with apigenin (0–80 μM) resulted in a dose‐dependent reduction in both cell number and cellular protein content, compared with untreated control cultures. DNA flow cytometric analysis indicated that treatment with apigenin resulted in G2/M arrest in all three cell lines in a time‐ and dose‐dependent manner. Apigenin treatment (80 μM) for 48 h produced maximum G2/M arrest of 64%, 42%, and 26% in SW480 cells, HT‐29 cells, and Caco‐2 cells, respectively, in comparison with control cells (15%). The proportion of S‐phase cells was not altered by apigenin treatment in each of the three cell lines. The G2/M arrest was reversible after 48 h of apigenin treatment in the most sensitive cell line SW480. The degree of G2/M arrest by apigenin was inversely correlated with the corresponding inhibition of cell growth measurements in all three cell lines (r = −0.626 to −0.917, P≤0.005). Moreover, an immune complex kinase assay demonstrated an inhibition of p34cdc2 kinase activity, a critical enzyme in G2/M transition, in each cell line after treatment with apigenin (50–80 μM). Western blot analyses indicated that both p34cdc2 and cyclin B1 proteins were also decreased after apigenin treatment. These results indicate that apigenin inhibits colon carcinoma cell growth by inducing a reversible G2/M arrest and that this arrest is associated, at least in part, with inhibited activity of p34cdc2 kinase and reduced accumulation of p34cdc2 and cyclin B1 proteins. Differences in induction of G2/M arrest by apigenin in the three colon carcinoma cell lines suggest that dietary apigenin may be differentially effective against tumors with specific mutational spectra. Mol. Carcinog. 28:102–110, 2000. © 2000 Wiley‐Liss, Inc.

Cytotoxicity of dietary flavonoids on different human cancer types

“…In this way, the epithelium of intestine is exposed to higher concentrations of flavonoids and their different metabolites than the tissues at other locations; and this would also be true for the colonic tumor cells, showing that colorectal cancer appears most relevant to dietary factors. [45127] At the same time, the exposure to different metabolites can explain the large fluctuations in cytotoxic constants of flavonoids measured using colorectal and liver cancer cell lines. It is possible that some metabolites could be more cytotoxic than parent compounds, giving a selective anticancer activity advantage in vivo .…”

“…The differential effectiveness of inhibition of cell growth and arresting cell cycle in response to flavonoids in various colorectal cancer cell lines may be associated with the functional status of p53 and/or ras genes. While apigenin has been indicated to have stronger effect on tumors with mutations in genes which are critical to colon cancer development, thus being more effective in controlling the growth of tumors with certain mutational spectra and less effective in wild-type normal cells,[2946127] kaempferol and hesperetin seem to exhibit higher resistance toward mutant p53 human colon cancer cell lines. [125128]…”

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Wang et al [65] were the first to report the effect of apigenin on cell growth in various human colon cancer cell lines [65]. Apigenin exposure to colon cancer cells demonstrated anti-proliferative effects, followed by reversible G2/M phase arrest in the cell cycle, and led to decreased levels of cyclin B1 and p34 (cdc2) protein levels.…”

Culinary Herbs and Spices: Their Bioactive Properties, the Contribution of Polyphenols and the Challenges in Deducing Their True Health Benefits

“…In addition, there is a growing amount of literature on the positive role of polyphenols and polyphenol rich foods on gut health specifically with regards to the prevention and treatment of colorectal cancer [84,105,106,107,108,109,110,111,112,113,114,115] However, there are a number of additional factors that need to be considered when attempting to elucidate the action of the gut on these foods and their polyphenols. First, in the study by Chohan et al .…”