The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review

Abstract

Autophagy is an evolutionarily conserved process for the degradation of redundant or damaged cellular material by means of a lysosome-dependent mechanism, contributing to cell homeostasis and survival. Autophagy plays a multifaceted and context-dependent role in cancer initiation, maintenance, and progression; it has a tumor suppressive role in the absence of disease and is upregulated in cancer cells to meet their elevated metabolic demands. Autophagy represents a promising but challenging target in cancer treatment. Green tea is a widely used beverage with healthy effects on several diseases, including cancer. The bioactive compounds of green tea are mainly catechins, and epigallocatechin-gallate (EGCG) is the most abundant and biologically active among them. In this review, evidence of autophagy modulation and anti-cancer effects induced by EGCG treatment in experimental cancer models is presented. Reviewed articles reveal that EGCG promotes cytotoxic autophagy often through the inactivation of PI3K/Akt/mTOR pathway, resulting in apoptosis induction. EGCG pro-oxidant activity has been postulated to be responsible for its anti-cancer effects. In combination therapy with a chemotherapy drug, EGCG inhibits cell growth and the drug-induced pro-survival autophagy. The selected studies rightly claim EGCG as a valuable agent in cancer chemoprevention.

Keywords: autophagy; autophagy activator; autophagy modulator; cancer therapy; epigallocatechin gallate.

Figure 1

Main categories of bioactive components of green tea. Abbreviations: catechin (C), catechin gallate (CG), epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), gallocatechin (GC), gallocatechin gallate (GCG), and epigallocatechin gallate (EGCG).

Figure 2

Origin of epigallocatechin gallate. (a) Chemical structure of epigallocatechin (EGC, above) and gallic acid (below), the two reactants that form epigallocatechin gallate (EGCG) via esterification of the circled functional groups. (b) Chemical structure of epigallocatechin gallate (EGCG), the major constituent of green tea catechins. Background: C. sinensis leaves, from which green tea extracts are produced. The two hydroxylated aromatic rings a and b are connected by a cyclic pyran ring, c; the aromatic ring d is part of the galloyl moiety, the distinctive element of the gallate derivatives of catechins.

Figure 3

Impact of EGCG on cancer-related signaling pathways. Components of ERK, PI3K-Akt, and 67-LR pathways (from right to left side of the image) are displayed. EGCG interference on ERK and PI3K-Akt pathways may depend on EGCG interaction with a receptor tyrosine kinase (RTK) or PTEN upregulation. EGCG binding to 67-LR may also induce acid sphingomyelinase (αSMase) activation and ceramide generation. See text in 2.1. subsection for a detailed description of the impacted signaling cascades and their implications. Red blunt arrows indicate negative regulation. Black arrows indicate positive regulation. Figure created with BioRender.com (accessed on 20 April 2022).

Figure 4

Overview of autophagy activation pathway under stressful or nutrient limiting conditions. The ULK initiation complex induces phagophore nucleation, and translocates to the endoplasmic reticulum or closely related membranes, where it phosphorylates and activates the class III phosphatidylinositol 3-kinase (PI3K) complex, thus producing phosphatidylinositol-3-phosphate (PI3P) on the isolation membrane. PI3P recruits specific autophagy effectors that contribute to ATG12-ATG5-ATG16L1 complex formation, which promotes microtubule-associated protein 1A/1B-light chain 3 (LC3) in conjugation with phosphatidyl-ethanolamine (PE), with the participation of ATG proteins. When the isolation membrane elongates and closes to form the autophagosome, lipidated LC3 (LC3-II) is integrated in the autophagosome, thus becoming a common autophagosome marker. As the autophagosome matures, it fuses with the lysosome to produce the autophagolysosome, where the inner membrane of the autophagic vesicle and its content are degraded by lysosomal hydrolases. Reduced signaling from MAPK and PI3K/Akt pathways on autophagy initiation is represented with dashed arrows. Black arrow and red blunt arrows represent positive and negative regulation, respectively. Figure created with BioRender.com (accessed on 20 April 2022).