Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications

Abstract

An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of its safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and its mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Structures of green tea catechins.

Fig. 2

Mechanism of actions of EGCG.

Fig. 3. Possible modulation of NF-kB pathway by EGCG

In the cytosol as a result of the binding of p50 and p65 to I-kB, NF-kB becomes inactive. When I-kB is phosphorylated by IKKs and degraded in a proteasome-dependent pathway, p50 and p65 are set free and are translocated into the nucleus to activate a specific set of genes. In vitro and in vivo this pathway has been shown to be inhibited by EGCG both, possibly by inhibiting IKK-catalyzed phosphorylation of I-kB.

Fig, 4. Different DNA methylation patterns, and histone modifications between normal and tumor cells

Molecular modeling of the interaction between EGCG and DNMT. In normal cells (a), genes are generally unmethylated and packaged with acetylated histone proteins associated with HAT as well as basal transcription factor machinery. These epigenetic elements constitute an ‘open’ chromatin structure which favors transcription. In cancer cells, the same genes may become hypermethylated (b), and the methylated CpG sites are recognized by the methyl-binding proteins (MBDs), which are coupled with repressor (R) and histone deacetyltransferase (HDAC) proteins to remove the acetyl group from the histones, generating a tightly closed chromatin status to shut down gene expression. (c) DNMT activity is blocked by EGCG through forming hydrogen bonds with amino acids (Pro, Glu, Cys, Ser, and Arg) in the catalytic pocket of DNMT. Newly synthesized DNA strands are hemi-methylated after the first round of DNA replication and become progressively more demethylated after several rounds of replication due to the dilution effect. Using EGCG as a DNMT inhibitor, the silenced epigenetic modifications could be switched to an active status.

Fig. 5. Impact of EGCG on microRNA (miRNA) expression

miRNA are transcribed in the nucleus into pri-miRNA (primary miRNA) which is further cleaved by Drosha into precursor miRNA (pre-miRNA). Pre-miRNA is exported from nucleus to the cytoplasm and further processed by Dicer into miRNA duplex. Single strand of miRNA duplex (also called mature miRNA) leads this complex to mRNA cleavage or translation repression, which is dependent on miRNA:mRNA complementarity. Dependent on various factors, miRNA can have either an oncogenic role (called oncomiRNAs) if the target mRNA is a tumor suppressor gene, or a tumor suppressive role (tumor-suppressor miRNAs) if the target molecule is an oncogene. EGCG can impact on expression level of miRNAs and participate in gene expression regulation.