A comparative reverse docking strategy to identify potential antineoplastic targets of tea functional components and binding mode.

The main functional components of green tea, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin (EC), are found to have a broad antineoplastic activity. The discovery of their targets plays an important role in revealing the antineoplastic mechanism. Therefore, to identify potential target proteins for tea polyphenols, we have taken a comparative virtual screening approach using two reverse docking systems, one based on Autodock software and the other on Tarfisdock. Two separate in silico workflows were implemented to derive a set of target proteins related to human diseases and ranked by the binding energy score. Several conventional clinically important proteins with anti-tumor effects are screened out from the PDTD protein database as the potential receptors by both procedures. To further analyze the validity of docking results, we study the binding mode of EGCG and the potential target protein Leukotriene A4 hydrolase in detail. We indicate that interactions mediated by electrostatic and hydrogen bond play a key role in ligand binding. EGCG binds to the enzyme with certain orientation and conformation that is suitable for nucleophilic attacks by several electrical residues inside the enzyme's activity cavity. This study provides useful information for studying the antitumor mechanism of tea's functional components. The comparative reverse docking strategy presented generates a tractable set of antineoplastic proteins for future experimental validation as drug targets against tumors.

Chemoprevention of elite tea variety CFT-1 rich in EGCG against chemically induced liver cancer in rats.

Camellia sinensis (L.) O. Kuntze cv. CFT-1 is an elite tea variety bred by sexual hybridization with a high content of epigallocatechin-3-gallate (EGCG) as 134.2 mg/g (which is 2.54-fold that of the common variety). This study was to evaluate the chemopreventive effects of CFT-1 green tea infusion (CFT-1) against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats and its mechanisms. The results showed that CFT-1 had a superior inhibitory effect in NDEA-initiated hepatocarcinogenesis compared to that of common tea. CFT-1 significantly reduced the hepatic nodules incidence, size, and number and prevented the hepatic adenoma or hepatocellular carcinoma (HCC) formation. In particular, CFT-1-treated animals had the least incidence of HCC (8.33%) followed by common tea treatment (40.00%) and model control rats (87.50%). CFT-1 treatment significantly ameliorated abnormal liver function enzymes, reduced serum AFP, CEA, TSGF, and TNF-α levels, inhibited the dickkopf-related protein-1 expression, enhanced antioxidant capacity, suppressed the production of livers 8-hydroxy-2'-deoxyguanosine, and regulated hepatic phase I and II xenobiotic-metabolizing enzymes. Transcriptomic analysis of liver tissue suggested that compared to common tea, administration of CFT-1 regulated larger gene sets, which were located in several important pathways of antioxidants, inflammatory network, xenobiotic-metabolizing enzymes, apoptosis, cell proliferation, and metabolism associated with liver tumorigenesis. We identified some genes as potential molecular targets involved in the prevention of CFT-1 and found that CFT-1 inhibited inflammation response, proliferation, and accelerated apoptosis by inhibiting NF-κB and PI3K/Akt pathway. Thus, EGCG-rich CFT-1 green tea might be a potential choice for liver cancer prevention/treatment in the future.

Preventive effects of combinative natural foods produced by elite crop varieties rich in anticancer effects on N-nitrosodiethylamine-induced hepatocellular carcinoma in rats.

The World Cancer Research Fund International has released 32 anticancer effects (ACEs) that targeted every stage of cancer processes. Thus, we designed two formulas of natural food combination Diet I and Diet II, mainly produced by elite crop varieties rich in ACEs with different mixture ratios, and evaluated their cancer preventive effects on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. After 20 weeks of dietary intervention, Diet I and Diet II reduced incidence, size, and number of hepatic nodules (p < 0.01) and prevented hepatic tumor formation in NDEA-induced hepatocarcinogenesis rats. Low-grade hepatic dysplasia incidence was 20% for Diet II and 40% for Diet I, and apparent hepatocellular carcinomas (HCC) rates were both 0, while 90% HCC in control diet treatment group (p < 0.01). Diet I and Diet II ameliorated abnormal liver function enzymes, reduced serum alpha fetal protein, tumor-specific growth factor, dickkopf-related protein 1, tumor necrosis factor-alpha and interleukin-6 levels, regulated hepatic phase I and II xenobiotic-metabolizing enzymes, enhanced antioxidant capacity, suppressed NDEA-initiated oxidative DNA damage, and induced apoptosis coupled to down-regulation of proinflammatory, invasion, and angiogenesis markers. Daily intake of combination diet produced from ACEs-rich elite crop varieties can effectively prevent or delay occurrence and development of NDEA-induced hepatocarcinogenesis in rats.

Water extract of Hedyotis Diffusa Willd suppresses proliferation of human HepG2 cells and potentiates the anticancer efficacy of low-dose 5-fluorouracil by inhibiting the CDK2-E2F1 pathway.

Hedyotis Diffusa Willd (HDW), a Chinese herbal medicine, has been widely used as an adjuvant therapy against various cancers, including hepatocellular carcinoma (HCC). However, the underlying anticancer mechanisms are yet to be elucidated. In the present study, the anticancer effects of HDW were evaluated and the efficacy and safety of HDW combined with low-dose 5-fluorouracil (5-FU) were investigated. HepG2 cells were cultured in vitro and nude mouse xenografts were established in vivo. The proliferation of HepG2 cells was measured using the MTT method and flow cytometry. The mRNA and protein expression levels of cyclin-dependent kinase 2 (CDK2), cyclin E and E2F1 were examined using relative quantitative real-time PCR and western blot analysis, respectively. The results showed that water extract of HDW remarkably inhibited HepG2 cell proliferation in a dose-dependent manner via arrest of HepG2 cells at the G0/G1 phase and induction of S phase delay. This suppression was accompanied by a great decrease of E2F1 and CDK2 mRNA expression. In addition, HDW remarkably potentiated the anticancer effect of low-dose 5-FU in the absence of overt toxicity by downregulating the mRNA and protein levels of CDK2, cyclin E and E2F1. Our findings support the use of HDW as adjuvant therapy of chemotherapy and suggest that HDW may potentiate the efficiency of low-dose 5-FU in treating HCC.