Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications

Abstract

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exert anti-proliferative, anti-inflammatory, and apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical and clinical studies suggest that EGCG may be used in the treatment of numerous disorders, including cancer. This review aims to summarize the existing knowledge regarding the biological properties of EGCG, especially in the context of cancer treatment and prophylaxis.

Keywords: bioavailability; clinical trials; epigallocatechin gallate; signaling pathways.

Figure 1

Chemical structure of epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG). Created with BioRender.com, accessed on 29 March 2023.

Figure 2

The molecular basis of the anticancer mechanism of action of epigallocatechin-3-gallate (EGCG) related to the suppression of inflammation. Cyclooxygenase 2 enzyme (COX2) catalyzes the conversion of arachidonic acid to prostaglandins (PGEs), including PGE2. PGE2 stimulates the expression of anti-apoptotic BCL-2 protein and the nuclear factor NF-kappa-B (NF-κB)-mediated gene expression of vascular endothelial growth factor, interleukins (IL-6 and -8), matrix metalloproteinases (MMPs), and COX2. EGCG was shown to act as a COX2, PGE2, NFκB, and MMPs inhibitor, suppressing the angiogenesis and metastasis of cancer cells and enhancing apoptosis induction. Additionally, EGCG may work as phosphoinositide-3-kinase/RAC-alpha serine/threonine-protein kinase (PI3K/AKT), epithelial growth factor (EGFR), and vascular endothelia growth factor, which control NF-κB and MMPs activity and expression and confer enhanced proliferation, angiogenesis, and metastasis. Furthermore, EGCG treatment may down-regulate the expression of tumor necrosis factor α (TNF-α) and suppress the activation of tumor necrosis factor receptor (TNFR) signaling. For full protein names, see the abbreviations section. Red arrows indicate down-regulation of the protein expression or its inhibition. Created with BioRender.com, accessed on 29 March 2023.

Figure 3

The modulation of epigenetic targets by epigallocatechin-3-gallate (EGCG). Methylation of CpG islands and histone proteins works as a mark that confers the closed chromatin formation and transcriptional suppression of genes encoding proteins involved in tumor suppression, invasion and metastasis inhibition, and apoptosis induction. EGCG down-regulates and inhibits the activity of DNA methyltransferases (DNMT1, DNMT3A, and 3B) that introduce methyl groups to DNA. Moreover, EGCG was shown to inhibit the activity of histone deacetylases (HDACs) that counteract the introduction of acetyl groups to histone proteins via histone acetyltransferases (HATs). The introduction of acetyl groups to histone proteins (H3K9, H3K14, H4K5, H4K12, and H4K16) contributes to the open chromatin state and elevated expression of tumor suppressor proteins (CDH1, DAPK1, P12, P16INK4a, P27, and RARβ), proteins involved in apoptosis induction and cell death control (DR5, GAD153, and TP53), and TIMP-3, which inhibits the proteolytic activity of MMP-2 and MMP-9. For full protein names, see the abbreviations section. Created with BioRender.com, accessed on 29 March 2023.

Figure 4

Overview of inhibitory effects of EGCG on key signaling pathways associated with the development of cancer. The details can be found in the main text of the manuscript. For the full names of the proteins, see the abbreviations section. Created with BioRender.com, accessed on 29 March 2023.

Figure 5

Overview of EGCG’s metabolism. Based on [347,348,372,373,374]. A detailed description can be found in the main text of the article. For full names, see the abbreviations section. Created with BioRender.com, accessed on 29 March 2023.

Figure 6

Anticancer properties of EGCG. EGCG exhibits antioxidant, anti-inflammatory, anti-proliferative, and anti-metastatic properties through the inhibition or modulation of key signaling pathways in cells and targets of epigenetic machinery. Details can be found in the main text of this article. Based on [94]. Created with BioRender.com, accessed on 29 March 2023.