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Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106 Page 7 of 36

Figure 3. Pharmacological targets of epicatechin-3-gallate. EGCG affects various targets relevant to cancer prevention as shown in the
figure. EGCG attenuates oxidative stress by down-regulating reactive oxygen species; inflammatory factors such as NF-κB and COX-
2 are down-regulated. In addition, EGCG down-regulates several kinases, such as MAPK, JNK1, and ERK, and targets several growth
factors, such as IGF1R, HGFR, and VEGF, that abate tumor growth and progression. Apoptosis factors such as p53, p21 and caspase 3
are up-regulated by EGCG, and the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), HO-1, and Nrf2 are increased to reduce
oxidative stress. EGCG: epigallocatechin-3-gallate; NF-κB: nuclear factor-κB; COX: cyclooxygenase; MAPK: mitogen-activated protein
kinase; ERK: extracellular signaling regulated kinases; VEGF: vascular endothelial growth factor

agent-resistant cancer stem cells such as A549/CDDP (cisplatin-resistant cells) and 5-flurouracil-resistant
colorectal cancer cells have demonstrated the anti-cancer activity of EGCG [79,80] . Mechanistic evaluations
with various in vitro models have led to the recognition of MAPKs as an important molecular target for
EGCG [Figure 3]. These factors are associated with cell proliferation, differentiation, migration, senescence,
[81]
and apoptosis . ECGC inhibits signal regulated protein kinase and p38 phosphorylation. EGCG is also
associated with inducing apoptosis, inhibition of transcription factors like NF-κB and activator protein
[82]
(AP-1), and reduction of receptor tyrosine kinase activity .

ERK signaling
ERK is one of the major signaling cascades of the MAPK signaling pathway that is targeted by EGCG.
EGCG inhibits ERK activation in a concentration-dependent manner, suggesting its effectiveness as an anti-
cancer agent with several in vitro models. With MCF10A and MDA-MB-231 breast cancer cells, 5 µmol/L
[83]
EGCG inhibited hepatocyte growth factor-induced activation of ERK and AKT . In cervical tumor cell
lines, like HeLa, Caski and SiHa, EGCG inhibited phosphorylated ERK1/2 by 83% and Akt by 50% at a
[84]
concentration of 50 µmol/L .

Activation of nuclear factor-κB and activator protein signaling pathways
Nuclear factor-κB (NF-κB) plays a vital role in the regulation of several genes central for cellular responses
like inflammation, growth, and cell death. It is sequestered in cytoplasm in an inactive form and activated
on phosphorylation. AP-1, a transcription factor, is known to be involved in tumor promotion and
[85]
progression of cancer . EGCG exerts inhibitory effects on the binding of NF-κB to DNA and thereby
reduces inflammation and cell proliferation with in vitro models. However, concentrations required to
mediate these effects were between 10-100 µmol/L [86,87] . EGCG evidently reduces binding of AP-1 along
with NF-κB to DNA; a process which promotes MMP-9 for tumor progression. This has been demonstrated
[88]
[89]
with several in vitro studies using human breast cancer cells , gastric AGS cells , and bladder cancer
cells , in a dose-dependent manner, with concentrations ranging from 10 to 50 µmol/L.
[90]
c-Jun N-terminal kinase 1/2
JNK is involved in cancer cell apoptosis, although recent studies have indicated that Janus signaling
promotes cancer cell survival by acting synergistically with NF-κB, JAK/STAT, and other signaling