No abstract

Green tea is a popular drink consumed daily by millions of people around the world. Previous studies have shown that some polyphenol compounds from green tea possess anticancer activities. However, systemic evaluation was limited. In this study, we determined the cancer chemopreventive potentials of 10 representative polyphenols (caffeic acid, CA; gallic acid, GA; catechin, C; epicatechin, EC; gallocatechin, GC; catechin gallate, CG; gallocatechin gallate, GCG; epicatechin gallate, ECG; epigallocatechin, EGC; and epigallocatechin gallate, EGCG), and explored their structure-activity relationship. The effect of the 10 polyphenol compounds on the proliferation of HCT-116 and SW-480 human colorectal cancer cells was evaluated using an MTS assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry after staining with propidium iodide (PI)/RNase or annexin V/PI. Among the 10 polyphenols, EGCG showed the most potent antiproliferative effects, and significantly induced cell cycle arrest in the G1 phase and cell apoptosis. When the relationship between chemical structure and anticancer activity was examined, C and EC did not show antiproliferative effects, and GA showed some antiproliferative effects. When C and EC esterified with GA to produce CG and ECG, the antiproliferative effects were increased significantly. A similar relationship was found between EGC and EGCG. The gallic acid group significantly enhanced catechin’s anticancer potential. This property could be utilized in future semi-synthesis of flavonoid derivatives to develop novel anticancer agents.

Soybean isoflavones have been used as a potential preventive agent in anticancer research for many years. Genistein is one of the most active flavonoids in soybeans. Accumulating evidence suggests that genistein alters a variety of biological processes in estrogen-related malignancies, such as breast and prostate cancers. However, the molecular mechanism of genistein in the prevention of human colon cancer remains unclear. Here we attempted to elucidate the anticarcinogenic mechanism of genistein in human colon cancer cells. First we evaluated the growth inhibitory effect of genistein and two other isoflavones, daidzein and biochanin A, on HCT-116 and SW-480 human colon cancer cells. In addition, flow cytometry was performed to observe the morphological changes in HCT-116/SW-480 cells undergoing apoptosis or cell cycle arrest, which had been visualized using Annexin V-FITC and/or propidium iodide staining. Real-time PCR and western blot analyses were also employed to study the changes in expression of several important genes associated with cell cycle regulation. Our data showed that genistein, daidzein and biochanin A exhibited growth inhibitory effects on HCT-116/SW-480 colon cancer cells and promoted apoptosis. Genistein showed a significantly greater effect than the other two compounds, in a time- and dose-dependent manner. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of ATM/p53, p21waf1/cip1 and GADD45α as well as downregulation of cdc2 and cdc25A demonstrated by q-PCR and immunoblotting assay. Interestingly, genistein induced G2/M cell cycle arrest in a p53-dependent manner. These findings exemplify that isoflavones, especially genistein, could promote colon cancer cell growth inhibition and facilitate apoptosis and cell cycle arrest in the G2/M phase. The ATM/p53-p21 cross-regulatory network may play a crucial role in mediating the anticarcinogenic activities of genistein in colon cancer.

Ginseng is an herbal medicine used worldwide. It is reported to have a wide range of pharmacological activities because of a diversified group of steroidal saponins called ginsenosides. Compared to extensive pharmacological studies of ginseng, the pharmacokinetics, especially the metabolism of this herb, has received less attention. In this article we review the known pharmacokinetic data on ginseng. Understanding ginseng’s pharmacokinetics may reduce the potential for interactions in patients who use both ginseng and prescription medications. In addition, bioavailability after taking ginseng orally is low, and the metabolites of ginsenosides produced by gut microbiota may be biologically active. One ginseng metabolite, Compound K, and its potential for cancer chemoprevention is also discussed. An active ginseng metabolite may differ in distribution and clearance from its parent compound, and the parent compound and its metabolite may be bioactive by similar or different mechanisms. Thus, further investigation of ginseng metabolites is needed for predicting the therapeutic outcome with ginseng.

Compound K (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to inhibit cell growth in a variety of cancers. However, the mechanisms are not completely understood, especially in colorectal cancer (CRC). A xenograft tumor model was used first to examine the anti-CRC effect of CK in vivo. Then, multiple in vitro assays were applied to investigate the anticancer effects of CK including antiproliferation, apoptosis and cell cycle distribution. In addition, a qPCR array and western blot analysis were executed to screen and validate the molecules and pathways involved. We observed that CK significantly inhibited the growth of HCT-116 tumors in an athymic nude mouse xenograft model. CK significantly inhibited the proliferation of human CRC cell lines HCT-116, SW-480, and HT-29 in a dose- and time-dependent manner. We also observed that CK induced cell apoptosis and arrested the cell cycle in the G1 phase in HCT-116 cells. The processes were related to the upregulation of p53/p21, FoxO3a-p27/p15 and Smad3, and downregulation of cdc25A, CDK4/6 and cyclin D1/3. The major regulated targets of CK were cyclin dependent inhibitors, including p21, p27, and p15. These results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in CRC, suggesting that CK could be an active compound in the prevention or treatment of CRC.