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Review Article
Cancer preventive and therapeutic effects of EGCG, the major polyphenol
in green tea
Islam Rady
a,b
, Hadir Mohamed
a
, Mohamad Rady
b
, Imtiaz A. Siddiqui
a
, Hasan Mukhtar
a,
⇑
a
School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, WI 53706, USA
b
Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt
article info
Article history:
Received 14 November 2017
Accepted 6 December 2017
Available online 19 December 2017
Keywords:
Green tea
EGCG
Anti-cancer effects
Cancer nanochemoprevention
abstract
(-)-epigallocatechin-3-gallate (EGCG), the major bioactive catechin in green tea (GT) has been studied for
almost past thirty years as an agent initially for its cancer chemoprevention effects and then for its cancer
chemotherapeutic ability. This agent has shown considerable anti-cancer effects in a variety of preclinical
cell culture and animal model systems. However, its clinical application to human patients is hampered
by a variety of reasons that includes its stability and bioavailability. As a result, an increased number of
studies assessing the effects derived from the use of EGCG are been employed in combination with other
agents or by utilizing innovative carrier settings. Here, we summarize the current understanding of the
anticancer effects of EGCG and its effects with other combinations on different kinds of cancers.
Further, we also present the available information for the possible mechanism of action of EGCG.
Ó2017 Mansoura University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents
Introduction. . . . . ........................................................................................................ 1
EGCG anticancer effects . . . . . . . . . . . . . . ..................................................................................... 3
Induction of apoptosis . . . . . ........................................................................................... 3
Modulation of cellular proliferation. . . . . . . . . . . ........................................................................... 4
Inhibition of angiogenesis and related mechanisms . . . . . . . . . . . . . . . . . ........................................................ 4
Anticancer effects of EGCG combinations ..................................................................................... 6
Induction of apoptosis . . . . . ........................................................................................... 6
Modulation of cellular proliferation. . . . . . . . . . . ......................................................................... . 18
Inhibition of angiogenesis and related mechanisms . . . . . . . . . . . . . . . . . ....... ................................................ 18
Anticancer effects of EGCG combined with nanoparticls . . . . . . . ................................................................. 19
Conclusion . . . . . . ....................................................................................................... 19
Acknowledgements . . . . . . . . . . . . . . . . . . .................................................................................... 19
References . . . . . . ....................................................................................................... 20
Introduction
Cancer is a group of diseases involving abnormal cell growth
with the potential to invade or spread to other parts of the body
[1]. It is one of the major ailment effecting humankind and remains
as one of the leading causes of mortality worldwide, for instance,
above 10 million new patients are diagnosed with cancer every
year and over 6 million deaths are associated with it representing
roughly 12% of worldwide deaths [2]. Almost fifteen million new
cancer cases are thought to be diagnosed by year 2020 [2,3] which
is anticipated to be potentially increase to over 20 million by 2025
[2,4]. It is also anticipated that the growth and aging of the popu-
lation might be increase the new cancer cases to 21.7 million
within about 13 million cancer deaths by the year 2030 [5]. The
development of cancer is a multifactorial process [6] which can
https://doi.org/10.1016/j.ejbas.2017.12.001
2314-808X/Ó2017 Mansoura University. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⇑
Corresponding author at: Department of Dermatology, University of Wisconsin-
Madison, Medical Sciences Center, #B-25, 1300 University Avenue, Madison, WI
53706, USA.
E-mail address: hmukhtar@wisc.edu (H. Mukhtar).
Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
Contents lists available at ScienceDirect
Egyptian Journal of Basic and Applied Sciences
journal homepage: www.elsevier.com/locate/ejbas
be caused by external factors such as infectious organisms, envi-
ronmental pollutants, tobacco and an unhealthy diet or internal
factors such as hormones, inherited genetic mutations and
immune conditions may act together or singular to cause the incip-
ience of cancer [7]. Since cancer is associated with such high mor-
bidity and mortality worldwide, there is an urgent need to
determine ways of management of this ailment where the current
treatment modalities are mainly surgery, radiation based therapy,
chemotherapy, gene therapy and/or hormonal therapy [2]. Natural
products, especially those derived from plants, have been used to
help mankind sustain its health since the dawn of medicine [8].
Nowadays, just like in ancient times, natural compounds are still
determining factors in remedies [9].
Herbal medicine or Herbalism (also known as phytotherapy) is
the study of botany and use of plants intended for medicinal pur-
poses or for supplementing a diet, has been applied for thousands
of years, but researchers started to study their mode of action at
the molecular, cellular and tissue levels only recently [10–12].It
is also a firm belief that naturally occurring plant based natural
compounds when properly formulated and administered have a
key role in cancer management.
Chemoprevention, especially through the use of naturally
occurring phytochemicals capable of impeding the process of car-
cinogenesis at one or more steps, is an ideal approach for cancer
management [13]. Among natural compounds, ever since our ini-
tial work in describing its potential benefit against cancer, green
tea has been extensively studied worldwide in a variety of cancer
models and the resulting data has been very promising. Green
tea leaves comprises of a diverse number of components (Fig. 1)
that are demonstrated to be beneficial to human health. The green
tea polyphenols are flavonols, commonly known as catechins [14]
which are found in greater amounts in green tea than in black or
Oolong tea [15].
Tea catechins were first isolated by Michiyo Tsujimura in 1929
in Japan [16] and since then four main types of catechins have been
found in green tea leaves (Table 1): (-)-epigallocatechin-3-gallate
(EGCG) accounts for approximately 59% of the total catechins from
the leaves of the green tea, (-)-epigallocatechin (EGC) (19%), (-)-
epicatechin-3-gallate (ECG) (13.6%), and (-)-epicatechin (EC)
(6.4%) [17,18]. The functional and structural differences between
these catechins are attributed to the number of hydroxyl groups
on the B-ring (Fig. 2) and the presence or absence of a galloyl moi-
ety [18].
Among these catechins, EGCG is the most studied and is consid-
ered to play a crucial role in cancer-preventive and therapeutic
activities [19–23]. Several studies have been performed to examine
the effects of EGCG on various in vitro cancer-related molecular
targets and in vivo models for potential cancer chemoprevention
and therapy [24]. The overwhelming majority of these studies
observed that EGCG inhibits a vast array of anticancer molecular
targets (Fig. 3) and cancer-related cellular processes [25].
Despite accomplished outcomes in preclinical settings, its appli-
cability to humans has met with limited success for many reasons
including inefficient systemic delivery and bioavailability. Several
optimization approaches including utilization of nanoparticle
based delivery of EGCG have been utilized to circumvent the issues,
for instance, we in a seminal study [26] introduced the novel con-
cept of ‘‘nanochemoprevention” that utilizes nanotechnology for
enhancing the outcome of EGCG in cancer chemoprevention.
Combination therapy or polytherapy (versus monotherapy) is
therapy that consumes more than one medication. There has been
some emphasis on determining the effects of combining EGCG
with other dietary agents. Several studies have indicated that
anti-cancer efficacy and scope of action of the individual agents
can be further enhanced by combining them synergistically
with chemically similar or different compounds (Fig. 4). Such a
Fig. 1. Schematic drawing of green tea leaves composition.
2I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
combination might be effective in reducing the drug dosage and
resistance, and simultaneously exhibiting higher therapeutic out-
come [27–29]. Studies suggest that EGCG can synergistically inhi-
bit cancer cells in vitro and in vivo when combined with other
dietary agents (Table 2), such as [6]-gingerol [30], curcumin [31],
lovastatin [32], quercetin [33], sulforaphane [34], panaxadiol
[35], and pterostilbene [36]. Some evidence is also available for
combination with chemotherapeutic agents such as 5-
fluorouracil [37], capecitabine [38], cisplatin [39], docetaxel [40],
doxorubicin [41] and temozolomide [42], or other agents like
sodium butyrate [43], vitamin C and amino acids [44]. Combina-
tion of EGCG with these molecules can synergistically inhibit can-
cer cell proliferation [45,46], induce apoptosis [47,48] and suppress
tumor angiogenesis and growth [40] to name a few pathways that
are effected by such an amalgamation. This synergistic effect, on
one hand, may be associated with enhanced bioavailability of
EGCG [49]. Studies find that natural small molecules, such as quer-
cetin can increase the bioavailability of EGCG in vitro and in vivo
[33]. Current literature summarize the current understanding of
the anti-cancer effects of EGCG alone and in combination with
other dietary and pharmaceutical agents.
EGCG anticancer effects
Induction of apoptosis
Apoptosis is a genetically encoded program leading to cell death
that is involved in normal development and homeostasis through-
out the animal kingdom [50]. It is the main event that is known to
regulate the occurrence and/or spread of cancer [2]. The morpho-
logical characteristicsof apoptosis include cell shrinkage, nuclear
fragmentation, chromatin condensation and membrane blebbing
[50–52]. Apoptosis can undertake one or two pathways, intrinsic
and/or extrinsic pathway (s) [53]. Intrinsic pathway, also known
as mitochondrial pathway, can be induced through intracellular
stresses via DNA damage or oxidative stress leading to release of
mitochondrial Cytochrome C to form apoptosome complex [54].
This complex is composed of Cytochrome C, apoptotic protease
activating factor 1 (Apaf-1) and procaspase-9 [55], which activates
Caspase-9, Caspase-3 and Caspase-7 [56]. Otherwise, extrinsic
pathway or death receptor pathway can be induced by death
ligands Fas ligand (FasL), tumor necrosis factor
a
(TNF
a
) and
TNF-related apoptosis inducing ligand (TRAIL) [57]. These ligands
Table 1
Dried green tea composition.
Molecular group Component Molecular
Formula
MW
(g/mol)
Percent of dried
tea extract
Main Biological effects
Polyphenols
Catechins
Epicatechin C
15
H
14
O
6
290.26 30–42 Cancer prevention, antioxidant, antibacterial and
antiviral effects.Epicatechin-3-gallate C
22
H
18
O
10
442.37
Epigallocatechin C
15
H
14
O
7
306.27
Epigallocatechin-3-
gallate (EGCG)
C
22
H
18
O
11
458.375
Flavonols
Kaempferol C
15
H
10
O
6
286.23 5–10 Anti-histamine and anti-inflammatory effects.
Quercetin C
15
H
10
O
7
302.236
Myricetin C
15
H
10
O
8
318.2351
Depsides
Theogallin C
14
H
16
O
10
344.27 2–4 Inhibition of Influenza A viruses.
Chlorogenic acid C
16
H
18
O
9
354.31
Coumarylquinic acid C
16
H
18
O
8
338.312
Organic acids Ascorbic acid C
6
H
8
O
6
176.124 1–2 Anticancer effects.
Gallic acid C
7
H
6
O
5
170.12 0.5
Quinic acid C
7
H
12
O
6
192.17 2
Folic acid C
19
H
19
N
7
O
6
441.404 0.5
Other organic acids – – 4–5
Amino acids Theanine C
7
H
14
N
2
O
3
174.2 4–6 Neuronal cell protection and relaxation effect.
c
-aminobutyric acid C
4
H
9
NO
2
103.121 2–4 Decrease of blood pressure.
Methylxanthines Caffeine C
8
H
10
N
4
O
2
194.19 7–10 Increased alertness and a mild diuretic effects.
Theobromine C
7
H
8
N
4
O
2
180.164
Theophylline C
7
H
8
N
4
O
2
180.167
Carbohydrates Glycosides – – 10–15 Energy and prevent blood sugar increase.
Minerals Aluminium, fluorine, manganese, iron,
magnesium, potassium, phosphorus,
zinc, selenium and sodium.
– – 6–8 Regulators.
Volatiles Saponin C
58
H
94
O
27
1223.363 0.02–1 Anti-fungal, anti-inflammatory, and anti-allergy
properties.Linalool C
10
H
18
O 154.25
4-Cardinene C
15
H
24
204.357
Geraniol C
10
H
18
O 154.253
Nerolidol C
15
H
26
O 222.37
a
-Terpineol C
10
H
18
O 154.25
Cis-Jasmone C
11
H
16
O 164.246
Indole C
8
H
7
N 117.15
b-Inone C
13
H
20
O 192.302
1-Octanal C
8
H
16
O 128.215
Indole-3-Carbinol C
9
H
9
NO 147.18
b-Caryophyllene C
15
H
24
204.36
Vitamins Thiamine (B1) C
12
H
17
N
4
OS
+
265.355 – Maintenance of healthy skin and mucus membrane.
Riboflavin (B2) C
17
H
20
N
4
O
6
376.369
Niacin (B3) C
6
H
5
NO
2
123.111
Vitamin B6 C
8
H
11
NO
3
169.18
Vitamin E C
29
H
50
O
2
430.717
b-Carotene C
40
H
56
536.888
Chlorophyll – C
55
H
72
O
5
N
4
Mg 893.509 – Deodorizing effect, kidney stone prevention and
strengthens immune system.
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 3
bind to their cell surface receptors TNFR1 and TNFR2, death recep-
tor DR4 and DR5 and Fas causing sequential activation of Caspase-
8, Caspase-3 and Caspase-7 [58]. Moreover, apoptosis is regulated
by several proteins such as BCL-2 [59], BAX [60], BCL-XL [61], BCL-
XS [62] BAD [63], BAK [64], BID [65], BIM [66], PUMA [67], XIAP
[68], NOXA [69], SMAC [70], MCL-1 [71] and c-FLIP [72].
EGCG induced cell apoptosis (Table 3) through intrinsic mito-
chondrial pathway via activation of Caspase-9 in PC3 prostate can-
cer cells [47], MCF-7 breast cancer cells [73] and PANC-1, MIA-Pa-
Ca-2, Hs 766 T and AsPC-1 pancreatic cancer cells [48]. EGCG has
also been shown to induce apoptosis through extrinsic death
receptor pathway in MIA-Pa-Ca-2 pancreatic cancer cells via acti-
vation of Fas, DR5 and Caspase-8 [74]. In addition, EGCG downreg-
ulated the expression of anti-apoptotic proteins, such as BCL-2 in
PANC-1, MIA-Pa-Ca-2, Hs 766 T and AsPC-1 pancreatic cancer cells
[48], MDA-MB-231 breast cancer cells [75], NCI-H295 adrenal can-
cer cells [76] and PC-12 pheochromocytoma cells [77], BCL-XL in
PANC-1, MIA-Pa-Ca-2, Hs 766 T and AsPC-1 cells pancreatic cancer
cells [48] and NCI-H295 adrenal cancer cells [76], survivin in MCF-
7 breast cancer cells [73] and NUGC-3 gastric cancer cells [78]; and
XIAP in NCI-H295 adrenal cancer cells [76]. Also, EGCG was found
to upregulate the expression of pro-apoptotic proteins, including
Apaf-1 and BAD in NCI-H295 adrenal cancer cells [76] and BAK,
BAX, BCL-XS and PUMA in PANC-1, MIA-Pa-Ca-2, Hs 766T and
AsPC-1 pancreatic cancer cells [48]. Moreover, EGCG induced apop-
tosis through both intrinsic and extrinsic pathways, regulatory
proteins and endoplasmic reticulum stress via activation of
caspase-dependent, caspase-independent, death receptors, down-
regulation of anti-apoptotic proteins BCL-2, BCL-XL and XIAP and
upregulation of pro-apoptotic BAD and BAX in NCI-H295 human
adrenal cancer cells [76].
pEGCG is synthesized by modifying reactive hydroxyl groups
with peracetate groups and found to be converted as well as accu-
mulated into parental EGCG when cultured with MDA-MB-231
human breast cancer cell. pEGCG was found to inhibit significantly
tumor growth in vivo through apoptosis induction in tumor tissues
[79].
Modulation of cellular proliferation
Proliferation is an important part of cancer development and
progression manifested by altered expression and/or activity of cell
cycle related proteins [80]. Similarly, cell cycle is the process by
which cells progress and divide [2]. Cell cycle regulatory proteins
include cyclins, cyclin-dependent kinases (Cdks), CDK interacting
proteins (CIPs) such as p21, kinase inhibitory proteins (KIPs) such
as p27, Cdk inhibitors (INKs) such as p18 and other proteins, such
as p53 and survivin [80–83]. In cancer however this regulatory
process malfunctions which results in uncontrolled cell prolifera-
tion and ultimately growth and progression of the tumor [2]. Many
evidences are available where EGCG has been shown to regulate
the cell cycle machinery via cell cycle regulatory proteins, leading
to cell cycle arrest and inhibition of cellular proliferation.
EGCG can induce mostly G0/G1 cell cycle arrest [45,48,84–87]
while its combination with other agents has been shown to induce
G0/G1 [46], G2/S [45] and/or G2/M [43] cell cycle arrest in variety
of cancer models. In addition, EGCG induces G1 cell cycle arrest
through regulation of cyclin D1, cdk4, cdk6, p21 and p27 in
AsPC-1, Hs 766T, PANC-1 and MIA-Pa-Ca-2 pancreatic cancer cells
[48]. Similarly, EGCG inhibits cell proliferation of A549, H460 and
H1650 lung cancer cells through induction of G0/G1 cell cycle
arrest via inhibiting EGFR/cyclin D1 signaling [86]. Likewise, EGCG
inhibits cell proliferation in LNCaP and DU-145 prostate cancer
cells via cell-type-specific manner which may be mediated by
WAF1/p21-causing G0/G1-phase cell-cycle arrest [87]. In addition,
EGCG induces G1 cell cycle arrest in HeLa and CaSki cervical cancer
cells trough gene expression regulation [85,88]. Moreover, EGCG
also suppresses cyclin D1 and activate p21 via ERK, IKK and PI3K
signaling pathway in order to inhibit cell proliferation in HCT-
116, Caco-2, HT-29 and SW480 colorectal cancer cells [89]. EGCG
also induces cell cycle arrest in A431 skin cancer cells through inhi-
bition of Cip1/p21 without any changes in Kip1/p27, CDK2, and
cyclin D1 while there was a decrease in CDK4 only at low doses
[90,91].
Inhibition of angiogenesis and related mechanisms
Like all cells, cancer cells require a constant supply of nutrients
and oxygen in order to grow and divide [92], and thus without an
adequate blood supply cancers might not grow [93]. Angiogenesis
is the physiological process through which new blood vessels form
from pre-existing vessels [94]. Cancers induce angiogenesis by
secreting various growth factors such as vascular endothelial
growth factor (VEGF) which is the major contributor to angiogen-
esis, increasing the number of capillaries in a given network [95].
Inhibition of cancer angiogenesis is increasing the death of the
tumor tissue (necrosis) whereas the presence of tumor necrosis
within primary tumors is associated with angiogenesis responses
Fig. 2. Molecular structure green tea catechins.
4I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
[96–98]. Furthermore, cancer cell motility, migration and invasion
play fundamental roles in cancer metastasis [99]. Therefore,
inhibiting either cancer cell motility, migration or invasion impede
metastasis, which is the cause of over 90% of patient deaths [100].
EGCG has demonstrated potential efficacy in inhibiting angio-
genesis, necrosis, motility, invasion, migration and metastasis
markers in a variety of human cancers tested under preclinical
model systems. In A549 lung cancer cells, EGCG was observed to
inhibit angiogenesis and reduce xenograft tumor growth through
inhibiting IGF-1 via suppressing HIF-1
a
and VEGF protein expres-
sion [101–104], upregulation of endostatin expression [102], inhi-
bition of HPV-16 oncoprotein induced angiogenesis conferred by
cancer cells via inhibition of HIF-1
a
protein expression and HIF-
1
a
dependent expression of VEGF, IL-8, and CD31 and activation
of Akt [104]. In addition, EGCG inhibits nicotine-induced migration,
invasion through upregulation of HIF-1
a
, VEGF, COX-2, p-Akt and
p-ERK [105]. Similarly, in lung NCI-H460 cancer cells, EGCG Inhi-
bits angiogenesis through inhibition of HIF-1
a
protein expression
and HIF-1
a
dependent expression of VEGF, IL-8, and CD31 as well
as activation of Akt [104]. EGCG also was able to inhibit cell motil-
ity in vitro wound healing assay in H1299 and Lu99 lung cancer
cells [106]. In ovarian cancer, EGCG inhibited cell motility through
suppression of Hsp90 chaperone system in SKOV3 cells [107].On
breast cancer, only 10
l
M of EGCG was able to inhibit cell migra-
tion trough downregulation of VEGF expression in Hs578T breast
[130]. In NF639 breast cancer cells, EGCG inhibited branching col-
ony growth and cell invasion through induction of estrogen recep-
tor
a
expression via activating FOXO3a signaling [108]. EGCG
inhibits cell migration and invasion through downregulation of
VASP expression and Rac1 activity [109] in MCF-7 cancer cells.
EGCG also Inhibits cell invasion, motility and migration in MDA-
MB-231 through inhibition of EGF-induced MMP-9 via suppressing
FAK and ERK signaling pathways [110]. In oral cancer, in SCC-9
cells, EGCG inhibited invasion, epithelial-mesenchymal transition,
and tumor growth through downregulation of MMP-2, uPA, p-
FAK, p-Src, snail-1 and vimentin [111]. EGCG inhibits HGF-
induced cell growth and invasion through suppression of HGF/c-
Met signaling pathway [112]. Repressing of functional invadopodia
formation was done by EGCG to inhibit in vitro and in vivo invasion
in HSC-3 and YD-10B oral cancer cells FAK/Src signaling [113].In
Hypopharyngeal FaDu and laryngeal SNU-899 and SNU-1066 can-
cer cells, EGCG Inhibited HGF-induced cell growth and invasion
through suppression of HGF/c-Met signaling pathway [112]. In gas-
tric cancer, EGCG inhibited xenograft angiogenesis and tumor
growth in BGC-823 [40]. EGCG inhibited IL-6-induced angiogenesis
in vitro and in vivo through inhibition of VEGF expression via sup-
pressing Stat3 activity in AGS cells [114]. In SGC-7901 cancer cells,
EGCG inhibited tumor growth and angiogenesis through reducing
VEGF-induced endothelial cell proliferation, migration and tube
formation [115]. In squamous cell carcinoma, EGCG inhibited
HGF-induced cell growth and invasion through suppression of
HGF/c-Met signaling pathway in SCC VII/SF cells while it inhibited
xenograft tumor growth in vivo via rising apoptosis [112]. In hep-
atocellular carcinoma, in Hepa 1c1c7 cells, EGCG inhibited cell
motility via suppression of Hsp90 chaperone system [107]. In cer-
vical cancer, EGCG inhibited cell proliferation, invasion and migra-
tion in HeLa cells through downregulation of MMP-9 gene and
upregulation of TIMP-1 gene [85]. In colorectal cancer, EGCG inhib-
ited tumor growth in vitro in SW837 cells and in vivo and through
activation of VEGF/VEGFR axis via suppressing the expression of
HIF-1
a
and several major growth factors [116]. EGCG also inhib-
ited migration and proliferation in SW620 cells in vitro through
inactivation of PAR2-AP and factor VIIa and by the way inhibition
of the ERK1/2 and NF-
j
B pathways [117]. Moreover, EGCG inhib-
ited inhibits liver metastasis in vivo RKO colorectal cancer cells
experiments and suppresses angiogenesis and induces apoptosis
Fig. 3. Schematic drawing of the regulative actions of EGCG. This carton is based on the available literature about the anticancer effects of EGCG.
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 5
in liver metastasis [118]. EGCG inhibited Met signaling which helps
to attenuate tumor spread/metastasis, independent of H
2
O
2
-
related mechanisms in HCT-116 and HT-29 colorectal cancer cells
[119,120]. In bladder cancer, EGCG inhibited cell adhesion, migra-
tion and invasion in T-24 cells through downregulation of MMP-9
expression via blocking of NF-
j
B signaling pathway [121]. In eso-
phageal TE-8 and SKGT-4 cancer cells, EGCG reduced cell viability
and invasion in vitro through reduction of p-ERK1/2, c-Jun and
COX-2, and activation of caspase-3 whereas it inhibits tumor
growth in vivo through suppressing the expression of Ki67, p-
ERK1/2 and COX-2 [32]. In prostate cancer, EGCG inhibited cell
motility and invasion through inhibition of c-Met signaling via
altering the structure or function of lipid rafts in DU-145 cells
[122]. In addition, EGCG Inhibited tumor growth and angiogenesis
in CWR22Rv1 cells but promoting apoptosis of the prostate cancer
cells in vivo [123]. In BCaPT10 cancer cells, EGCG inhibited cell
motility in vitro via suppression of Hsp90 molecular chaperone sys-
tem which supports malignant phenotype [124]. EGCG-P is more
stable and effective than EGCG enhancing the inhibition of the
tumor growth, angiogenesis of CWR22Rv1 prostate cancer cells
in vivo [123].
Anticancer effects of EGCG combinations
Induction of apoptosis
Several studies have stated that EGCG and its combinations
have induced apoptosis in a variety of cancers. EGCG as a green
tea polyphenol (GTP) or combined with different natural molecules
have been employed to induce apoptosis in different cancers. The
general idea is that combination of two or more agents could target
more pathways and thus will be more effective to increase the sta-
bility of the agent and reduce toxicity to simultaneously exhibit
higher therapeutic outcome. Various studies found that EGCG syn-
ergistically induced cancer cells apoptosis in vitro and in vivo
through different apoptotic signaling, upregulation of pro-
apoptotic proteins and inhibition of anti-apoptotic proteins when
combined with other natural molecules, such as vitexin-2-O-
xyloside and raphasatin [46], curcumin [125],N-acetylcysteine
(NAC) [126], pterostilbene [36], tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) [74], quercetin [33], whole
green tea polyphenols (GTPs) [127], eicosapentaenoic acid-free
fatty acid (EPA-FFA) and grape seed [GS] extract [128],5-
fluorouracil (5-FU) [37], sodium butyrate (NaB) [43] and [6]-
Gingerol and tocotrienol-rich fraction (TRF) [30].
Combination of EGCG with curcumin induces apoptosis through
upregulation of caspase-dependent apoptotic signaling pathways
in MCF-7 breast cancer cells [125]. However, a mixture of EGCG,
vitexin-2-O-xyloside and raphasatin was found to induce apoptosis
via mitochondrial pathway in breast MDA-MB-231 and MCF-7 and
colorectal Caco-2 and LoVo cancer cells [46]. In addition, NAC and
EGCG interact to form EGCG-2
0
-NAC adduct which induces cell cul-
ture apoptosis in CL-13 lung cancer cells [126]. Also, pterostilbene
and EGCG combination induced apoptosis in both PANC-1 and
MIA-Pa-Ca-2 pancreatic cancer cells [36] Adding TRAIL to EGCG
increases synergistically apoptosis induction via cleavage of
procaspase-3 in MIA-Pa-Ca-2 cells [74]. Studies observed that nat-
ural small molecules, such as quercetin, can increase the bioavail-
ability of EGCG in rats and human [129] enhancing apoptosis
Fig. 4. Schematic drawing of the regulative actions of EGCG combined with other dietary and pharmaceutical agents. This carton is based on the available literature.
6I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
Table 2
Compounds have previously combined with EGCG.
Molecular structure Molecular
Formula
MW
(g/mol)
Cancers (cell lines)
[6]-Gingerol C
17
H
26
O
4
294.391 Glioma (SW1783, LN18 and
1321N1) [30]
Arginine C
6
H
14
N
4
O
2
174.204 Prostate (PC-3, LNCaP and
DU-145) [44] and bladder
(T-24) [137] cancers
Ascorbic acid C
6
H
8
O
6
or
HC
6
H
7
O
6
176.124
Curcumin C
21
H
20
O
6
368.385 Breast (MDA-MB-231 [31]
and MCF-7 [125,146]), lung
(A549 [45] and NCI-H460
[45]), prostate (PC-3) [33]
and nsophageal (TE-8 and
SKGT-4) [32] cancers
Green tea
polyphenols (GTP)
Epicatechin C
15
H
14
O
6
290.26 Prostate (LNCaP) cancer
[147]
Epicatechin-3-
gallate
C
22
H
18
O
10
442.37
Epigallocatechin C
15
H
14
O
7
306.27
Kaempferol C
15
H
10
O
6
286.23
Quercetin C
15
H
10
O
7
302.236 Prostate (PC-3 [33] and
LNCaP [33] [147]) cancer
Myricetin C
15
H
10
O
8
318.2351 Prostate (LNCaP) cancer
[147]
(continued on next page)
(continued on next page)
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 7
Table 2 (continued)
Molecular structure Molecular
Formula
MW
(g/mol)
Cancers (cell lines)
Theogallin C
14
H
16
O
10
344.27
Chlorogenic acid C
16
H
18
O
9
354.31
Coumarylquinic
acid
C
16
H
18
O
8
338.312
GS C
31
H
28
O
12
592.553 Colorectal (HCT-116 and
SW480) cancer[128]
Polyphenon E Caffeine C
8
H
10
N
4
O
2
194.194 Lung cancer [148]
(+)-
Gallocatechin
C
15
H
14
O
7
306.27
EGC
(+)-Catechin C
15
H
14
O
6
290.271
EC
8I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
induced against cancer cells due to EGCG treatment, such as in
LNCaP and PC-3 prostate cancer cells [33].In vivo GTPs (including
that contains EGCG) oral infusion resulted in significant apoptosis
of cancer cells causing inhibition of prostate cancer development,
progression, and metastasis [127]. A combination of EGCG, eicos-
apentaenoic acid-free fatty acid and grape seed extract [128] or a
mixture of EGCG and Fluorouracil (5-FU) [37] induced apoptosis
in both HCT-116 and SW480 colorectal cancer cells [37,128]. Also
apoptosis through survivin downregulation has been noted when
HCT-116, HT-29 and RKO colorectal cancer cells are treated with
a combination of EGCG and NaB [43]. Finally, both EGCG and [6]-
Gingerol or EGCG and TRF combinations both can induce apoptosis
in 1321N1, LN18 and SW1783 glioma cells through activation of
caspase-3 [30].
On the other hand, cancer stem cells (CSCs) have been identified
in a number of solid tumors, including breast cancer, brain tumors,
lung cancer, colon cancer, and melanoma [130]. CSCs have the
capacity to self-renew, to give rise to progeny that are different
from them, and to utilize common signaling pathways [130,131].
CSCs may be the source of all the tumor cells present in a malig-
nant tumor, the reason for the resistance to the chemotherapeutic
agent used to treat the malignant tumor, and the source of cells
Table 2 (continued)
Molecular structure Molecular
Formula
MW
(g/mol)
Cancers (cell lines)
()-
Gallocatechin
gallate
C
22
H
18
O
11
458.375
ECG
()-Catechin
gallate
C
22
H
18
O
10
442.376
EGCG
pterostilbene C
16
H
16
O
3
256.301 Pancreatic (PANC-1 and
MIA-Pa-Ca-2) cancer [36]
Sulforaphane C
6
H
11
NOS
2
177.28 Prostate (PC-3) cancer [34]
Tocotrienol-rich fraction (TRF) C
28
H
42
O
2
410.642 Glioma (1321N1, LN18 and
SW1783) [30]
TRAIL – – – Pancreatic (MIA-Pa-Ca-2)
cancer [74]
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 9
Table 3
Anticancer effects of EGCG alone and combination.
Cancers Cell lines EGCG Combination Dose & IC
50
Biological effects
Breast cancer MDA-MB-231 EGCG 50 and 100
l
M[149]; 50 and 80
l
g/
mL [75]; 20, 40 and 60
l
M[150];10
and 20
l
M[110]; 0.01–1000
l
M
[151].
IC
50
:50
l
M (24 h) [149], 15.7
l
M
[151]
Inhibits cell proliferation and viability through suppression of Wnt signaling via inducing the HBP1
transcriptional repressor [149], epigenetic repression of hTERT [150] and inhibition of glucose
uptake and metabolism [151]. Induces cell apoptosis through stimulation of pro-apoptotic
signaling and downregulation of MMP-9 expression [75]. Inhibits cell invasion, motility and
migration through inhibition of EGF-induced MMP-9 via suppressing FAK and ERK signaling
pathways [110].
pEGCG 20
l
M[150];50
l
mol/L [79] Inhibit cell proliferation via Epigenetic repression of hTERT [150]. In addition, it inhibits
significantly tumor growth in vivo associated with increased proteasome inhibition and apoptosis
induction in tumor tissues [79].
EGCG + Curcumin E (20,25,35 and 40
l
M) and/or C
(2,3,4 and 6
l
M)
Inhibits cancer proliferation in vitro and in xenograft mouse models through inhibition of VEGFR-1,
EGFR and AKT protein level [31].
EGCG (E) + Vitexin-2-O-
xyloside (X) + Raphasatin
(G)
E (10,20,30,40,50
l
g/mL),
(30,50,80, 100,120
l
g/mL) and/or G
(5,10,15,30,50
l
g/mL).
IC
50
: E (135 ± 16), X (158 ± 13), G (36
±5)
l
g/mL
Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
induces apoptosis [46].
EGCG-Ptx-PLGA-Casein-NPs – Induce apoptosis, inhibite NF-
j
B activation and downregulate the key genes associated with
angiogenesis, tumor metastasis and survival [141].
EGCG-LbL-PSS/PAH-NPs 1 or 5
l
M[152] Inhibit HGF-induced c-Met signaling after prolonged pre-incubation [13,152].
MCF-7 EGCG 10, 20, 30, 40 and 50 [73]; 10, 25, 50
and 100 [109]; 1 and 10
l
M[153];
20, 40 and 60 [150]; 0.01–1000
l
M
[151]; 10, 20 and 40
l
M[154]; 0.1, 1,
10, 50 and 100
l
M[146].IC
50
:50
l
g/
mL [73,109]; 44.1
l
M[151] 40
l
M
[154]; 19–20
l
M[146]
Induces growth inhibition and apoptosis through surviving expression downregulation via
suppressing AKT pathway and activation of caspase-9 [73]. Inhibits cell migration and invasion
through downregulation of VASP expression and Rac1 activity [109]. Inhibits nicotine and
estradiol-induced cell proliferation via downregulation of
a
9-nicotinic acetylcholine receptor
signaling pathway [153]. Inhibits cell viability and proliferation through epigenetic repression of
hTERT [150], inhibition of glucose uptake and metabolism [151], epigenetic downregulation of ER-
a
via p38MAPK/CK2 activation [154] and activation of Cav3.2 channels via elicit of Ca2 + spike
[146].
pEGCG 20
l
M[150] Inhibit cell proliferation via epigenetic repression of hTERT [150]
EGCG + Curcumin E (2, 4, 10, 20, 40, 100)
l
M+C20
l
M Induce growth inhibition and apoptosis through upregulation of caspase-dependent apoptotic
signaling pathways and inhibition of P-glycoprotein pump function [125].
EGCG (E) + Vitexin-2-O-
xyloside (X) + Raphasatin
(G)
E (10,20,30,40,50
l
g/mL), X
(30,50,80, 100,120
l
g/mL) and G
(5,10,15,30,50
l
g/mL); IC
50
: E (135 ±
16), X (158 ± 13), G (36 ± 5)
l
g/mL
Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
induces apoptosis [46].
Hs578T EGCG 10
l
M Inhibits cell proliferation and migration trough downregulation of VEGF expression [155].
T47D EGCG 10, 20 and 40
l
M.
IC
50
:40
l
M
Inhibits cell proliferation trough epigenetic downregulation of ER-
a
via p38MAPK/CK2 activation
[154].
NF639 EGCG 20, 40, 60 and 80 mg/mL [156];40
l
g/
mL [108]
Inhibits Her-2/Neu signaling, proliferation, and transformed phenotype of the Cancer Cells [156].
Inhibit branching colony growth and cell invasion through induction of estrogen receptor
a
expression via activating FOXO3a signaling [108].
4 T1 EGCG 10 mg/kg, IP injection on day 7, 9 and
11
Suppresses tumor growth in vivo by inhibiting tumor-associated macrophage infiltration and M2
polarization [157].
ALDH1
+
in SUM-149
and SUM-190 stem
cells
EGCG 20, 40, 80 and 120
l
g/mL Inhibits growth of cancer stem cells in vitro and in vivo. Inhibits spheroid formation and induces
apoptosis [133].
CD44
+
/CD24
in MDA-
MB-231 and MDA-MB-
436 stem cells
EGCG 20, 30 and 40
l
M Inhibits tumorsphere formation and reduces cancer stem cell population through downregulation
of estrogen receptor-
a
36, EGFR, p-ERK1/2 and p-AKT [158].
10 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
Lung Cancer A549 EGCG 40–300
l
M, IC
50
: 265 ± 7.1
l
M (24 h)
in vitro and 40 mg/kg/week by IP
injection into BALB/c nude female
mice for 33 days [101]. 50 and 100
l
Min vitro and 0.05% in drinking
water into BALB/c nude male mice for
21 days [102]. 1, 5, 10, 20 and 40
l
M
[159]. 10, 25, 50 and 100 [104,105].
10–40
l
M[86].80
l
M[160]. 25 and
100 [161]. 100
l
M into flanks of nude
mice [103–105]. 5,10,25 and 50 [162]
Induces cell apoptosis through inhibition of FASN activity and EGFR signaling pathway [101].
Reduces xenograft tumor growth and angiogenesis in vivo [101,102]through inhibiting of oncogene
and IGF-1via suppressing HIF-1
a
and VEGF protein expression [103,104]. Inhibits cell proliferation
through upregulation of endostatin expression and suppression of VEGF expression [102] and
suppressing of the expression of the cell death-inhibiting gene, Bcl-xL [161]. Inhibits cell growth
through induction of G0/G1 cell cycle arrest via inhibiting EGFR/cyclin D1 signaling [86] and
upregulation of miR-210 expression via stabilizing HIF-1
a
[162]. Inhibits the anchorage-indepen-
dent growth of cancer cells, induces p53 accumulation and upregulates its target genes, promotes
the stability of p53 and MDM2, promotes nuclear localization and activity of p53, inhibits
proteasomal degradation-dependent p53 ubiquitination and inhibits the interaction of p53 and
MDM2 [159]. Inhibits HPV-16 oncoprotein induced angiogenesis conferred by cancer cells through
the inhibition of HIF-1a protein expression and HIF-1a dependent expression of VEGF, IL-8, and
CD31 as well as activation of Akt [104]. Inhibits cancer chemo-resistant variants through
downregulation of Axl and Tyro 3 expression [160]. Inhibits nicotine-induced migration, invasion
and upregulation of HIF-1
a
, VEGF, COX-2, p-Akt and p-ERK [105].
EGCG + Curcumin 10,20,40
l
M EGCG and/or the same
concentrations for curcumin in vitro
while fourteen 3 to 4-week old
female BALB/c nude mice were i.p.
implanted with 5 106 A549 cells.
At the third day after the A549 cells
injected, the mice were randomized
into two groups (7 mice/group) and
treated with control (NS, 100 mL/kg)
or EGCG and curcumin (20 mg/kg,
respectively) [45]
Inhibit cell growth in vitro and in vivo through induction of cell cycle arrest at G1 and S/G2 phases
via downregulating cyclin D1 and cyclin B1 [45].
CL13 EGCG 5,10,25 and 50 Suppresses cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-
1
a
[162].
EGCG + N-acetylcysteine
(NAC)
(0–100)
l
M of EGCG in the presence
or absence of 0–2 mM NAC.
EGCG and NAC interact to form EGCG-2
0
-NAC adduct which induces cell culture apoptosis [126].
H1299 EGCG 10,20,30,40 and 50
l
Min vitro, 0.1,
0.3 and 0.5% in diets and 30 mg/kg/d
by IP injection into male NCr nu/nu
mice for 45 days.
IC
50
:20
l
Min vitro and 0.15
l
M
in vivo [163]; 5,10,25 and 50 [162]
Inhibits cancer growth in vivo and in vitro and induces ROS and cell apoptosis [163]. Suppresses
cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1
a
[162].
H460 EGCG 1,5,10,20 and 40
l
M[159]. 10–40
l
M
[86].80
l
M[160]. 5,10,25 and 50
[162]
Inhibits the anchorage-independent growth of cancer cells, induces p53 accumulation and
upregulates its target genes, promotes the stability of p53 and MDM2, promotes nuclear
localization and activity of p53, inhibits proteasomal degradation-dependent p53 ubiquitination
and inhibits the interaction of p53 and MDM2[159]. Inhibits cell growth through induction of G0/
G1 cell cycle arrest via inhibiting EGFR/cyclin D1 signaling [86]. Inhibit cancer cells proliferation
including their chemo-resistant variants through downregulation of Axl and Tyro 3 expression
[160]. Suppresses cancer cell growth through upregulating miR-210 expression caused by
stabilizing HIF-1
a
[162].
H1650 EGCG 1,5,10,20 and 40
l
M[159]. 10–40
l
M
[86]
Inhibits the anchorage-independent growth of cancer cells, induces p53 accumulation and
upregulates its target genes, promotes the stability of p53 and MDM2, promotes nuclear
localization and activity of p53, inhibits proteasomal degradation-dependent p53 ubiquitination
and inhibits the interaction of p53 and MDM2 [159]. Inhibits cell growth through induction of G0/
G1 cell cycle arrest via inhibiting EGFR/cyclin D1 signaling [86].
H1299 EGCG 5,10,50 and 100
l
M[106] Reduces cell motility in vitro wound healing assay. Increases Young’s modulus of H1299 from 1.24
to 2.25 showing a 2-fold increase in cell stiffness, i.e. rigid elasticity of cell membrane. Furthermore,
inhibits high expression of vimentin and Slug in the cells at a leading edge of scratch. Induces
inhibition of EMT phenotypes by alteration of membrane organization [106].
Lu99 EGCG Reduces cell motility in vitro wound healing assay. Increases Young’s modulus of Lu99 from 1.29 to
2.28 showing a 2-fold increase in cell stiffness, i.e. rigid elasticity of cell membrane. Furthermore,
inhibits high expression of vimentin and Slug in the cells at a leading edge of scratch. Induces
inhibition of EMT phenotypes by alteration of membrane organization [106].
(continued on next page)
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 11
Table 3 (continued)
Cancers Cell lines EGCG Combination Dose & IC
50
Biological effects
H69 EGCG 20,40,50,60,80,100,120,140,150 and
200
l
M. IC
50
:70
l
M (24 h)
Induces cell apoptosis, reduces telomerase activity and inducts a cell-cycle block in S phase [164].
H69VP
NCI-H460 EGCG 10,25,50 and 100 in vitro [104] Inhibits HPV-16 oncoprotein induced angiogenesis conferred by cancer cells through the inhibition
of HIF-1a protein expression and HIF-1a dependent expression of VEGF, IL-8, and CD31 as well as
activation of Akt [104].
EGCG + Curcumin 10,20,40
l
M EGCG and/or the same
concentrations for curcumin
Inhibit cell growth in vitro and in vivo through induction of cell cycle arrest at G1 and S/G2 phases
via downregulating cyclin D1 and cyclin B1 [45].
– EGCG + Polyphenon E Benzo(a)pyrene [B(a)P]-induced lung
cancer in female A/J mice (100 mg/
kg).
Mixture inhibits significantly pulmonary adenoma formation and growth in vivo [148].
Pancreatic cancer AsPC-1 EGCG 5–80
l
M[48] Induces apoptosis through cell cycle via G1 cell cycle arrest, regulation of cyclin D1, cdk4, cdk6, p21
and p27, activation of ROS-mediated, p53-indepdendent apoptosis signaling, inhibition of Ras/Raf-
1/ERK1/2 signaling, induction of MEKK1, JNK1/2 and p38 MAPK activities [48].
Hs 766 T
PANC-1 EGCG 5–80
l
M[48]
EGCG + Pterostilbene 20, 30 and 40
l
M EGCG with/without
30
l
M Pterostilbene
The combination have additive, antiproliferative effects in vitro altering the apoptotic mechanisms
by modulation at different points in the mechanism as well as the cell cycle arrest effect [36].
MIA-Pa-Ca-2EGCG 10, 100 and 1000
l
M, IC
50
below 50
l
M[165]; 5–80
l
M[48]
Induces apoptosis through cell cycle via G1 cell cycle arrest, regulation of cyclin D1, cdk4, cdk6, p21
and p27, activation of ROS-mediated, p53-indepdendent apoptosis signaling, inhibition of Ras/Raf-
1/ERK1/2 signaling, induction of MEKK1, JNK1/2 and p38 MAPK activities [48]. Inhibits Hsp90
function by impairing Hsp90 association with co-chaperones resulting anti-proliferating effects
[165].
EGCG + TRAIL 50
l
g/ml E+5 ng/ml T A synergistic increase in apoptosis and cleavage of procaspase-3. Furthermore, clonogenic cell
survival assay demonstrates the significant diminishment of cancer cell proliferation in the
presence of both EGCG and TRAIL [74].
EGCG + Pterostilbene 20, 30 and 40
l
M EGCG with/without
30
l
M Pterostilbene
The combination have additive, antiproliferative effects in vitro altering the apoptotic mechanisms
by modulation at different points in the mechanism as well as the cell cycle arrest effect [36].
Ovarian cancer SKOV3 EGCG 20,30,40 and 50
l
g/mL [166];
20,40,60,80,100 and 120
l
g/mL
[167]; 100
l
M[107]
Inhibits cell proliferation and induces apoptosis through inhibition of cell cycle and DNA synthesis
inducting NDA damage [166]. Downregulates AQP5, nuclear p65 and I
j
-B
a
expressions [167].
Inhibit cell motility via suppression of Hsp90 chaperone system [107].
Oral cancer SAS EGCG 20 and 40
l
M[168] Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
via blocking the IFN-
c
-induced JAK-PKC-d-STAT1 signaling pathway [168].Cal-27
Ca-922
SCC-9 EGCG 5,10,15 and 20
l
Min vitro; 10 and 20
mg/day/kg by oral gavage into the
right front axilla of BALB/c nude mice
Inhibits invasion, epithelial-mesenchymal transition, and tumor growth through downregulation of
MMP-2, uPA, p-FAK, p-Src, snail-1 and vimentin [111].
SCC-4 EGCG 20 and 40
l
M[168]; 10, 20, 50, 100,
and 200
l
M[169]
Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
via blocking the IFN-
c
-induced JAK-PKC-d-STAT1 signaling pathway [168]. Suppresses cell
proliferation and promotes apoptosis and autophagy through upregulation of BAD, BAK, FAS, IGF1R,
WNT11, and ZEB1 genes expressions and downregulation of CASP8, MYC, and TP53 [169].
KB EGCG 5,10,20,40,80,100,150 and 200
l
M Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
pathway [112].
HSC-3 EGCG 20 and 40
l
M[168]; 10,25,50 and
100
l
M[113]
Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
via blocking the IFN-
c
-induced JAK-PKC-d-STAT1 signaling pathway [168]. Inhibits cancer invasion
via repressing functional invadopodia formation [113].
YD-10B EGCG 10,25,50 and 100
l
Min vitro; 20 mg/
d/kg IP injection into the tongue of
male BALB/c athymic nude mice
every other day for 4 weeks
Inhibits cancer invasion in vitro and in vivo via repressing functional invadopodia formation and
FAK/Src signaling [113].
Hypopharyngeal
cancer
FaDu EGCG 5,10,20,40,80,100,150 and 200
l
M Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
pathway [112].
Laryngeal cancer SNU-899 EGCG 5,10,20,40,80,100,150 and 200
l
M Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
pathway [112].SNU-1066
Nasopharyngeal
cancer
(Oct4
high
/Nanog
high
/b-
catenin
high
/ABCG2
high
/
MRP-1
high
/MDR-1
high
)
in TW01 CSCs
EGCG+Cisplatin (20 and 40
l
M) E and/or (0.01, 0.1, 1
and 10
l
g/mL) C
Mixture inhibits spheroid formation and cell viability as well as EGCG enhances chemo-sensitivity
of cisplatin in vitro through downregulation of Oct4, b-Catenin, Nanog, ABCG2, MRP-1, MDR-1, p-
STAT3, Bcl-2, Survivin and c-Myc [170].
(Oct4
high
/Nanog
high
/b-
catenin
high
/ABCG2
high
/
MRP-1
high
/MDR-1
high
)
in TW06 CSCs
12 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
CNE2 EGCG + Cisplatin EGCG (20
l
M) + Cisplatin (10
l
M)
were injected subcutaneously into
the flanks of nude mice and allowed
to grow for 8 weeks
EGCG increases chemo-sensitivity of cisplatin in vivo [138].
CD44
+
in CNE2 CSCs EGCG 25,50 and 75
l
M Inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial–
mesenchymal transition via NF-
j
B p65 inactivation [138].
C666-1 EGCG + Cisplatin EGCG (20
l
M) + Cisplatin (10
l
M)
were injected subcutaneously into
the flanks of nude mice and allowed
to grow for 8 weeks
EGCG increases chemo-sensitivity of cisplatin in vivo [138].
CD44
+
in C666-1 CSCs EGCG 25,50 and 75
l
M Inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial–
mesenchymal transition via NF-
j
B p65 inactivation [138].
Gastric cancer BGC-823 EGCG 1.5 mg/d IP injection for 56 days Inhibits xenograft angiogenesis and tumor growth [40].
EGCG + Docetaxel –
EGCG + Capecitabine 200 mg/kg capecitabine daily by oral
gavage + EGCG (IP injection of 1.5 mg
EGCG daily
Inhibits xenograft angiogenesis and tumor growth [38].
AGS EGCG 5,10,25 and 50
l
Min vitro and 50
l
M
EGCG + AGS cells in vivo into BALB/c
nude female mice for 7 days [114];
20,40,60,80,120 and 240
l
g/mL [171]
Inhibits IL-6-induced angiogenesis in vitro and in vivo through inhibition of VEGF expression via
suppressing Stat3 activity [114]. Inhibits cell proliferation and induces cell apoptosis through
downregulation of Id1 expression [171].
AZ521 EGCG 5,10,20 and 40
l
M Inhibits cell proliferation through downregulation of DEAD-box RNA helicase p68 [172].
NUGC-3 EGCG 25,50,75 and 100
l
M Induces cell apoptosis through inhibition of survivin expression downstream of p73 [78].
MKN-1
MKN-28
MKN-45
TMK-1
SGC-7901 EGCG 1.5 mg/d IP injection into female
BALB/c nude for 28 days
Inhibit tumor growth and angiogenesis through reducing VEGF-induced endothelial cell
proliferation, migration and tube formation [115].
Hepatocellular
Carcinoma
Hepa 1c1c7 EGCG 100
l
M Inhibit cell motility via suppression of Hsp90 chaperone system [107].
SMMC-7721 EGCG + Ascorbic acid – Mixture strongly suppress proliferation and metastasis through scavenging of reactive oxygen
species [136].
HepG2 EGCG 15,30,60,120 and 240 Induces non-apoptotic cell death via ROS-mediated lysosomal membrane permeabilization [173].
EGCG + 5-FU 5-FU (0.05
l
g) and EGCG (25
l
mol) Combination significantly decreased the viability of cells, compared with EGCG or 5-FU-treated
cells [174].
CD133 and NANOG in
HepG2 cancer stem
cells
EGCG 10 and 20
l
M Inhibit sphere formation through inhibition of CD133, Nanog, ABCC1, ABCG2, Nek2 and p-Akt [174].
Squamous cell
carcinoma
SCC VII/SF EGCG 5,10,20,40,80,100,150 and 200
l
M
in vitro; 25,50 and 75 mg/kg/day IP
injection into the flank of syngeneic
C3H/HeJ micefor 21 days
Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
pathway while it inhibits xenograft tumor growth in vivo via rising apoptosis [112].
Prostate cancer PC-3 EGCG 0–50
l
M. IC
50
: 39.0
l
M Antiproliferative effects through ERK1/2 activation via MEK-independent, PI3-K-dependent
signaling pathway [175].
1 and 25
l
M. IC
50
:25
l
M Induces cell apoptosis through upregulation of caspase-9a expression [47].
EGCG + Curcumin 50 and 100
l
M E and/or 50
l
M C Induction of cell cycle arrest at both S and G2/M phases via upregulating p21 protein level [135].
EGCG + Quercetin 80
l
M EGCG and/or 10 and 20
l
M
Quercetin
Mixture demonstrates enhanced inhibition of cell proliferation and induction of cell apoptosis
in vitro by increasing the intracellular concentration of EGCG and decreasing EGCG methylation
[33].
EGCG + Sulforaphane 20 and 100
l
M E and/or 25
l
M S Reduction of cell viability via inhibition of AP-1 activation [34].
EGCG + Ascorbic acid +
Lysine + Proline + Arginine
50 microg/mL-500
l
g/mL of the
mixture
Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
9 expressions [44].
EGCg-
198
AuNPs single-dose intra-tumoral
administration in human prostate
cancer-bearing SCID mice
80% reduction of tumor volumes after 28 d demonstrating significant inhibition of tumor growth
compared to controls [176].
EGCG-LDH nanohybrids 25,50,75 and 100
l
M/L; IC
50
: 16.66
l
M/L (24 h), 15.47
l
M/L (48 h),
16.33
l
M/L (72 h)
Induce apoptosis within over 5-fold dose advantages compared to EGCG alone in in-vitro system
[142].
(continued on next page)
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 13
Table 3 (continued)
Cancers Cell lines EGCG Combination Dose & IC
50
Biological effects
EGCG-PLA-PEG-NPs 0.7,1.37,2.74 and 5.48
l
mol/L in vitro,
IC
50
: 3.74
l
mol/L (24 h); in vivo, mice
each received 100
l
g dissolved in PBS
thrice weekly [26]
NPs enhance the bioavailability and limited unwanted toxicity of EGCG within 10-fold dose
advantage [13]. In addition, induce apoptosis within remarkably significant increase in pro-
apoptotic Bax with a concomitant decrease in anti-apoptotic Bcl-2, increase in PARP cleavage and
marked induction of p21 and p27 [26].
EGCG-PLGA-PEG-DCL-NPs 20
l
MIn vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
EGCG-PLGA-PEG-AG-NPs
PC-3ML EGCG + Doxorubicin 30 and 60
l
ME+Din vitro; 0.14–57
mg/kg E and/or 2 mol/L–0.07 mg/kg
D into immunodeficiency mice
Combination enhances the inhibition of metastatic tumor growth [41].
(CD44
+
CD133
+
in PC-3)
CSC
EGCG 30 and 60
l
M Inhibits growth and spheroid formation, induces apoptosis, inhibits EMT, inhibits migration and
invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP, Vimentin, Slug, Snail and nuclear b-
Catenin [132].
LNCaP EGCG 12
l
M[177]; 20,40 and 80
l
M[178];
10, 20, 40, and 80
l
g/mL [87]
Modulates cell growth, by affecting mitogenesis as well as inducing apoptosis, in cell-type-specific
manner which may be mediated by WAF1/p21-caused G0/G1-phase cell-cycle arrest, irrespective
of the androgen association or p53 status of the cells [87].Inhibits cell proliferation through
inhibition of PKC-
a
inhibition [177], prostate specific antigen (PSA) expression, AR transcriptional
activity, growth of relapsing R1Ad tumors and tumor derived serum PSA in vivo [178].
Green tea polyphenols
(GTP)
10–80
l
g/mL In vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase1
[147].
EGCG + Quercetin 80
l
M EGCG and/or 10 and 20
l
M
Quercetin
Quercetin enhances the anti-proliferative effects of EGCG and induction of cell apoptosis in vitro
through increasing the intracellular concentration of EGCG and decreasing EGCG methylation [33].
EGCG + Ascorbic acid
+Lysine+Proline+Arginine
50 microg/mL–500
l
g/mL of the
mixture
Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
9 expressions [44].
EGCG-PLGA-PEG-DCL-NPs 20
l
MIn vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
EGCG-PLGA-PEG-AG-NPs
(CD44
+
CD133
+
in
LNCaP) CSCs
EGCG 30 and 60
l
M Inhibits growth and spheroid formation, induces apoptosis, inhibits EMT, inhibits migration and
invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP, Vimentin, Slug, Snail and nuclear b-
Catenin [132].
DU-145 EGCG 5
l
M; 10, 20, 40, and 80
l
g/mL [87] Modulates cell growth, by affecting mitogenesis as well as inducing apoptosis, in cell-type-specific
manner which may be mediated by WAF1/p21-caused G0/G1-phase cell-cycle arrest, irrespective
of the androgen association or p53 status of the cells [87].
Inhibit cell motility and invasion through inhibition of c-Met signaling via altering the structure or
function of lipid rafts [122].
EGCG + Ascorbic acid +
Lysine + Proline + Arginine
50 microg/mL–500
l
g/mL of the
mixture
Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
9 expressions [44].
EGCG-PLGA-PEG-DCL-NPs 20
l
MIn vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
EGCG-PLGA-PEG-AG-NPs
CWR22R EGCG 50 mg/kg/d IP injection into nude
mice for 20 days.
Inhibits tumor growth and angiogenesis while promoting apoptosis of the prostate cancer cells
in vivo [123].
EGCG-P 86.7 mg/kg/d IP injection into nude
mice for 20 days.
EGCG-P is more stable and effective than EGCG enhancing the inhibition of the tumor growth,
angiogenesis and induces apoptosis of the prostate cancer cells in vivo [123].
BCaPT10 EGCG 2–200
l
Min vitro; 0.06% in water
into male athymic mice for 1 week
before xenograft surgery
Inhibits cell motility in vitro via suppression of Hsp90 molecular chaperone system which supports
malignant phenotype [124].
BCaPM-T10 EGCG 0.06% in water into male athymic
mice for 1 week before xenograft
surgery
Inhibits a molecular chaperone supportive of the malignant phenotype [124].
22R
m
1 EGCG-CS-NPs 3 and 6 mg/kg by oral administration
into athymic nude mice for 25 days
Inhibit AR-positive 22R
m
1 tumor xenograft growth and secreted prostate-specific antigen levels
compared with EGCG and control groups. Significant induction of poly (ADP-ribose) polymerases
cleavage, increase in the protein expression of Bax with concomitant decrease in Bcl-2, activation of
caspases and reduction in Ki-67 and proliferating cell nuclear antigen [143].
– EGCG Five-week-old male TRAMP offspring
were fed AIN-76A diet and 0.06%
EGCG in tap water for28 weeks
Inhibits cell proliferation and induces apoptosis through downregulation of AR, IGF-1, IGF-1R, p-
ERK 1/2, COX-2, and iNOS [179].
14 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
– GTP – In vivo GTP oral infusion resulted in almost complete inhibition of distant site metastases.
Furthermore, GTP consumption caused significant apoptosis of cancer cells causing inhibition of
prostate cancer development, progression, and metastasis [127].
Melanoma Mel 928 EGCG-CS-NPs 0.5,1.0,2.0,4.0 and 8.0
l
Min vitro;
IC
50
:7
l
M (48 h). 100
l
g/mice;120
l
L treatment volume into Athymic
(nu/nu) male nude mice.
Induct apoptosis and cell cycle inhibition along with the growth of Mel 928 tumor xenograft.
Inhibited proliferation (Ki-67 and PCNA) and induced apoptosis (Bax, PARP) in tumors harvested
from the treated mice within 8-fold dose advantage of nanoformulation over native EGCG [144].
Leukemia CEM (MSN@EGCG)-NPs 0.4, 0.8, 1.2 and 1.6
l
Min vitro and
100; NPS are i.v. injected into female
Balb/c mice
Inhibit cell viability and proliferation in vitro and in vivo within a highly biocompatible and
biodegradable EGCG-coated MSN nanoparticles [180].
Cervical cancer HeLa EGCG 10, 25, 50 and 100
l
M[88];
10,20,30,40,50,60,70,80,90 and 100
l
M[85];IC
50
: 47.9
l
M[88]; 100
l
M
(24 h) and 50
l
M (48 h) [85].
Cell growth inhibition trough gene expression regulation and induction of cell cycle arrest [88].
Inhibit cell proliferation, invasion and migration, and induce cell apoptosis through G1 cell cycle
arrest and DNA damage, downregulation of MMP-9 gene and upregulation of TIMP-1 gene [85].
CaSki EGCG 10, 25, 50 and 100
l
M. IC
50
: 27.3
l
M
(24 h)
Cell growth inhibition trough gene expression regulation and induction of cell cycle arrest [88].
Colorectal cancer HCT-116 EGCG 0.05, 0.1, 0.5, 1, 5 and 10
l
M[119];
0.1, 0.5, 1, 5 and 10
l
M[120];1,10
and 50
l
M[89]; 50 and 100
l
M
[181]; 12.5,25,50 and 100
l
M[118].
IC
50
:3
l
M[119]
Suppresses cancer cells growth through cyclin D1 degradation and p21 transcriptional activation
via ERK, IKK and PI3K signaling pathway [89]. Inhibits Met signaling [119] which helps to attenuate
tumor spread/metastasis, independent of H
2
O
2
-related mechanisms [120]. Inhibits cell prolifera-
tion through inhibition of HGF-induced Met/ERK/AKT signaling pathway [119]and through
inhibition of Akt, activation and induction of p38 MAPK activation [118]. Induces cell apoptosis
through cancer-specific induction of ROS and epigenetic modulation of expression of apoptosis-
related genes, such as hTERT [181].
EGCG + Panaxadiol E (0,10,20 and 30
l
M) and/or P (0,10
and 20
l
M)
Inhibit cell proliferation and induce cell cycle arrest [35].
EGCG + EPA-FFA + GS EGCG (0–175
l
M) + EPA-FFA (0–150
l
M) + GS extract (0–15
l
M) for 24 h
Combination completely inhibited the mTOR signaling. Moreover, the treatment led to changes of
protein translation of ribosomal proteins, c-Myc and cyclin D1. In addition, combination reduces
clonal capability of cells, with block of cell cycle in G0/G1 and induction of apoptosis [128].
EGCG + 5-FU 5-FU (0.05
l
g) and EGCG (25
l
mol)
[174]; 25–400
l
M of EGCG and/or
2.5–40
l
M 5-FU [37].
Combination significantly decreased the viability of cells, compared with EGCG or 5-FU-treated
cells [174] like the EGCG enhances 5-FU sensitivity and induces apoptosis in 5-FU resistant cancer
cells [37].
EGCG + NaB 10
l
M E +(1,2,3,4,5 and 6 mM) N.
IC
50
:10
l
M E + 5 mM N
The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
HDAC1, DNMT1, survivin and HDAC activity [43].
CD133 and NANOG in
HCT-116 stem cells
EGCG 10 and 20
l
M Inhibit sphere formation through inhibition of CD133, Nanog, ABCC1, ABCG2, Nek2, and p-Akt
[174].
CD44, CD133 and
ALDH1 in HCT-116
stem cells
EGCG 50, 100, 200 and 400
l
M Induces apoptosis and cell cycle arrest, attenuate spheroid formation and enhance
chemosensitivity of 5-FU in vivo [37].
HCT-8 EGCG 10,20 and 35
l
g/mL [182] Inhibits proliferation in vitro and in vivo, induces apoptosis and affects cell cycle of cancer cells via
inhibiting of HES1 and Notch2 expressions [182].
Caco-2 EGCG 1, 5 and 10
l
M[183]; 1, 10 and 50
l
M[89]
Induces cell growth inhibition as EGCG and 67LR at a physiological concentration can activate
myosin phosphatase by reducing MYPT1 phosphorylation [183] or through cyclin D1 degradation
and p21 transcriptional activation via ERK, IKK and PI3K signaling pathway [89].
EGCG (E) + Vitexin-2-O-
xyloside (X) + Raphasatin
(G)
E (10,20,30,40,50
l
g/mL), X
(30,50,80, 100,120
l
g/mL) and G
(5,10,15,30,50
l
g/mL);
IC
50
: E (135 ± 16), X (158 ± 13), G (36
±5)
l
g/mL
Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
induces apoptosis [46].
EGCG-CS-CPP-NPs 0.063, 0.125 and 0.250 mg/mL Nanoparticles enhance stability, penetration and transportation of EGCG through cancer cells [184].
HT-29 EGCG 0.1, 0.5, 1, 5 and 10
l
M[120];1,10
and 50
l
M[89]; 10,20 and 35
l
g/mL
[182]; 5, 10 and 20 mg/kg/d oral
gavage to male BALB nude mice for
28 days [185] or/14 days [182].
Inhibits Met signaling and helps to attenuate tumor spread/metastasis, independent of H
2
O
2
-
related mechanisms [120]. Suppresses cancer cells growth through cyclin D1 degradation and p21
transcriptional activation via ERK, IKK and PI3K signaling pathway [89]. Inhibits proliferation
in vitro and in vivo and induces apoptosis and affectes the cell cycle of cancer cells via inhibiting of
HES1 and Notch2 expressions [182]. Inhibit tumor growth and metastasis in vivo by upregulating
the Nrf2-UGT1A signaling [185].
EGCG + NaB 10
l
M E + (1,2,3,4,5 and 6 mM) N.
IC
50
:10
l
M E + 5 mM N
The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
HDAC1, DNMT1, survivin and HDAC activity [43].
(continued on next page)
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 15
Table 3 (continued)
Cancers Cell lines EGCG Combination Dose & IC
50
Biological effects
SW837 EGCG 25
l
g/mL in vitro; 0.01% and 0.1% in
drinking water to BALB/c nude mice
for 35 days [116]; 10,50 and 100
l
M
[186]
Inhibits tumor growth in vivo and in vitro through activation of VEGF/VEGFR axis via suppressing
the expression of HIF-1
a
and several major growth factors [116]. Provides antitumor
immunotherapy through inhibiting the expression and function of indoleamine 2,3–dioxygenase
via suppression of STAT1 activation [186].
SW480 EGCG 1, 10 and 50
l
M[89]; 10,20 and 35
l
g/mL [182]
Suppresses cancer cells growth through cyclin D1 degradation and p21 transcriptional activation
via ERK, IKK and PI3K signaling pathway [89]. Inhibits proliferation in vitro and in vivo and induces
apoptosis and affectes the cell cycle of cancer cells via inhibiting of HES1 and Notch2 expressions
[182].
EGCG + Panaxadiol E (0,10,20 and 30
l
M) and/or P (0,10
and 20
l
M)
Inhibit cell proliferation and induce cell cycle arrest [35].
EGCG + EPA-FFA + GS EGCG (0–175
l
M) + EPA-FFA (0–150
l
M) + GS extract (0–15
l
M) for 24 h
Combination completely inhibits the mTOR signaling and lead to changes in protein translation of
ribosomal proteins, c-Myc and cyclin D1 and reduces clonal capability of cells, with block of cell
cycle in G0/G1 and induction of apoptosis [128].
EGCG + 5-FU 25–400
l
M of EGCG and/or 2.5–40
l
M 5-FU [37].
EGCG enhances 5-FU sensitivity and induces apoptosis in 5-FU resistant cancer cells [37]
SW620 EGCG 25,50,75 and 100
l
g/mL Inhibits proliferation and migration in vitro through inactivation of PAR2-AP and factor VIIa and by
the way inhibition of the ERK1/2 and NF-
j
B pathways [117].
LoVo EGCG 10,20 and 35
l
g/mL Inhibits proliferation in vitro and in vivo and induces apoptosis and affects the cell cycle of cancer
cells via inhibiting of HES1 and Notch2 expressions [182].
EGCG (E) + Vitexin-2-O-
xyloside (X) + Raphasatin
(G)
E (10,20,30,40,50
l
g/mL),
(30,50,80, 100,120
l
g/mL) and G
(5,10,15,30,50
l
g/mL); IC
50
: E (135 ±
16), X (158 ± 13), G (36 ± 5)
l
g/mL
Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
induces apoptosis [46].
RKO EGCG 12.5,25,50 and 100
l
Min vitro;30
mg/kg IP injection to SCID male mice
every other day for 2 weeks [118]
Inhibits cell proliferation and induces cell apoptosis through inhibition of Akt, activation and
induction of p38 MAPK activation; inhibits liver metastasis in vivo and suppresses angiogenesis and
induces apoptosis in liver metastasis [118].
EGCG + NaB 10
l
M E + (1,2,3,4,5 and 6 mM) N.
IC
50
:10
l
M E + 5 mM N
The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
HDAC1, DNMT1, survivin and HDAC activity. Furthermore, p53-dependent induction of p21 and an
increase in nuclear factor kappa B (NF-kB)-p65 [43].
– EGCG-(poly[lactic-co-
glycolic acid])-NPs
– Modify DNA damage in human lymphocytes from colon cancer patients and healthy individuals
treated in vitro with platinum-based chemotherapeutic drugs [187].
Glioma 1321N1 EGCG 50,100,150,200,250 and 300
l
g/mL;
IC
50
: 82.0 ± 10.31
l
g/mL (24 h)
Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
EGCG + [6]-Gingerol 50
l
g/mL EGCG + GING; IC
50
:40±
8.62
l
g/mL
Mixture inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
EGCG + Tocotrienol-rich
fraction (TRF)
100
l
g/mL EGCG + TRF; IC
50
: 100 ±
9.5
l
g/mL
LN18 EGCG 50,100,150,200,250 and 300
l
g/mL;
IC
50
: 134.0 ± 11.36
l
g/mL (24 h)
Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
EGCG + [6]-Gingerol 50
l
g/mL EGCG + GING; IC
50
:24±
2.65
l
g/mL
Mixture inhibits proliferation and induces apoptosis through activation of caspase-3[30].
EGCG + Tocotrienol-rich
fraction (TRF)
80
l
g/mL EGCG + TRF; IC
50
:88±
11.14
l
g/mL
SW1783 EGCG 50,100,150,200,250 and 300
l
g/mL;
IC
50
: 300.0 ± 9.10
l
g/mL (24 h)
Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
EGCG + [6]-Gingerol 60
l
g/mL EGCG + GING; IC
50
:60±
5.6
l
g/mL
Mixture inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
EGCG + Tocotrienol-rich
fraction (TRF)
100
l
g/mL EGCG + TRF; IC
50
: 270 ±
4.16
l
g/mL
U87 EGCG + Temozolomide 100
l
M E + 100
l
M TMZ EGCG inhibits properties of glioma stem-like cells (CD133
high
/ALDH1
high
) and synergizes with TMZ
through downregulation of P-glycoprotein inhibition [42].U251
SHG-44
C6
16 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
Skin cancer A431 EGCG 5, 10, 20, 40, and 80
l
g/mL [90];100–
200
l
M[91]; 10,20,40 and 60
l
g/mL
[188]
Inhibits cell growth, viability and induces cell apoptosis [90,91] through inhibition of EGFR
signaling [91], inhibition of pRb-E2F/DP pathway [90], inducing cell cycle arrest [90,91], inhibition
of Cip1/p21 but no change in Kip1/27, CDK2, and cyclin D1 and a decrease in CDK4 only at low
doses [91] and inactivation of b-catenin signaling [188].
SCC-13 EGCG 10,20,40 and 60
l
g/mL [188];
10,20,40,60 and 100
l
M[189]
Reduces cell viability [188], induces cell apoptosis [188,189] and inhibits cell growth [189] through
inactivation of b-catenin signaling [188] and influencing PcG-mediated epigenetic regulation of cell
cycle-related genes [189].
– Green tea polyphenols 200
l
L of a 5% solution Prevent the adverse effects of UV radiation in humans [190].
Esophageal cancer TE-8 EGCG 40
l
Min vitro Reduces cell viability and invasion in vitro through reduction of p-ERK1/2, c-Jun and COX-2, and
activation of caspase-3 whereas it inhibits tumor growth in vivo through suppressing the
expression of Ki67, p-ERK1/2 and COX-2 [32].
EGCG (E) + Curcumin (C) E (40
l
mol/L), C (40
l
mol/L), and L (4
l
mol/L) in vitroEGCG (E) + Curcumin (C) +
Lovastatin (L)
SKGT-4 EGCG 40
l
Min vitro and 50
l
g/kg/d by oral
intake into nude mice for 30 days (5
day/week)
EGCG (E) + Curcumin (C) E (40
l
mol/L), C (40
l
mol/L), and L (4
l
mol/L) in vitroEGCG (E) + Curcumin (C) +
Lovastatin (L)
Adrenal cancer NCI-H295 EGCG 10, 20, 30 and 40 mMin vitro;IC
50
:
20.34 mM (48 h)
Induces cell apoptosis through activation of caspase-dependent, caspase-independent, the
mitochondrial, death receptor and endoplasmic reticulum stress apoptotic signaling pathways.
EGCG also downregulate the expression of anti-apoptotic proteins, including BCL-2, BCL-XL and
XIAP. It upregulate the expression of pro-apoptotic proteins, including Apaf-1, BAD and BAX. It
regulate molecular chaperones, such as 70 kDa heat shock protein (HSP70), HSP90 and GRP78 [76].
Bladder cancer T-24 EGCG 10, 20, 40, 80 mg/mL Inhibit cell adhesion, migration and invasion through downregulion of MMP-9 expression via
blocking of NF-
j
B signaling pathway [121].
EGCG (in green tea extract)
+ Ascorbic acid + Lysine +
Proline + Arginine
10,50,100,500 and 1000 mg/mL of the
mixture
Mixture inhibits critical steps of cancer development and spread, such as MMP-2 and -9 secretions
and invasion [137].
Pheochromocytoma PC-12 EGCG 15 mg/kg IP injection into male BALB/
c nude mice every other day for 15
days
Inhibits tumor growth and induces cancer cell apoptosis via acetylation of amyloid precursor
protein [77].
Neuroblastoma (Nanog
high
/Oct4
high
/
ATP7A
low
/DKK2
low
)in
BE(2)-C CSCs
EGCG 1,10,50 and 100
l
M Inhibits the development of TICs in BE(2)-C cells as well as inhibits sphere formation and induces
apoptosis [134].
Ehrlich’s ascites
carcinoma
EAC EGCG + HDHA-DOX-NPs E (20 mg/kg b.wt., orally through
gavage) + HDHA-DOX-NPs (1.5 mg/kg
b.wt.) intravenously into Swiss albino
mice.
EGCG enhances the anticancer activities of HDHA-NPs significantly increasing the mean survival
time of the animals and inducing apoptosis [145].
Head and neck
squamous
carcinoma (HNSC)
CSCs
K3 EGCG + Cisplatin 5,10,20 and 50
l
M E and/or 5,10 and
20
l
MC
Inhibit sphere formation and CD44
+
cell population; enhances chemosensitivity of cisplatin in vitro
and in vivo through downregulation of Oct4, Sox2, ABCC2, ABCG2 and Notch1 [39].K4
K5
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 17
that give rise to distant metastases [130]. Recently, studies found
that EGCG can induce apoptosis to inhibit CSCs in vitro and
in vivo. Besides, its effect of spheroid formation inhibition in CSCs,
it induces apoptosis, and enhances chemo-sensitivity of chemo-
drugs in CSCs, for instance, EGCG induces apoptosis through down-
regulating Casp3/7, Bcl-2, survivin and XIAP in PC-3 and LNCaP
prostate CSCs [132]. In addition, EGCG treatment induced apopto-
sis in the breast SUM-149 and SUM-190 CSCs [133], colon HCT-116
CSCs [37] and neuroblastoma BE(2)-C CSCs[134], and enhance the
chemosensitivity of 5-FU in vivo [37].
Modulation of cellular proliferation
On the other hand, EGCG and curcumin combination inhibits
cell proliferation and growth in vitro and in vivo in lung A549
and NCI-H460 cancer cells through induction of cell cycle arrest
at G1 and S/G2 phases via downregulating cyclin D1 and cyclin
B1 [45] while same combination induces cell cycle arrest at both
S and G2/M phases via upregulating p21 protein level in PC-3 pros-
tate cancer cells [135]. EGCG, vitexin-2-O-xyloside and raphasatin
mixture induces G0/G1 cell cycle arrest in MDA-MB-231 and MCF-
7 breast, Caco-2 and LoVo colorectal cancer cells [46]. EGCG and
pterostilbene combination has antiproliferative effects in vitro as
a cell cycle arrest induction in pancreatic PANC-1 and MIA-Pa-
Ca-2 cancer cells [36]. Similarly, EGCG and panaxadiol mixture
inhibit cell proliferation and induce cell cycle arrest in both HCT-
116 and SW480 colorectal cancer cells [35]. EGCG, EPA-FFA and
GS combination blocks cell cycle in G0/G1 in both HCT-116 and
SW480 colorectal cancer cells [128]. EGCG and NaB combination
treatment induces G2/M cell cycle arrest through decreasing sur-
vivin in HCT-116, HT-29 and RKO colorectal cancer cells [43]. Fur-
thermore, EGCG inhibit cell proliferation via induction of cell cycle
arrest and attenuate spheroid formation in colorectal HCT-116
CSCs [37].
Inhibition of angiogenesis and related mechanisms
EGCG combinations has also been observed to inhibit angiogen-
esis, necrosis, motility, invasion, migration and metastasis in
experimental cancer systems. In vivo GTP oral infusion resulted
Fig. 5. Schematic drawing of the regulative actions of EGCG combined with nanoparticles. This carton is based on the available literature.
18 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
in almost complete inhibition of distant site metastases in prostate
cancer. Furthermore, GTP consumption caused significant apopto-
sis of cancer cells causing inhibition of prostate cancer develop-
ment, progression, and metastasis [127]. A combination of EGCG
and curcumin or EGCG, curcumin and lovastatin was able to reduce
cell viability and invasion in vitro in TE-8 and SKGT-4 esophageal
cancer cells through reduction of p-ERK1/2, c-Jun and COX-2, and
activation of caspase-3 whereas it inhibited tumor growth in vivo
through suppressing the expression of Ki67, p-ERK1/2 and COX-2
[32]. EGCG and doxorubicin mixture enhanced the inhibition of
metastatic tumor growth in PC-3ML prostate cancer cells [41].
EGCG, ascorbic acid, lysine, proline and arginine combination
inhibited cell proliferation and invasion through downregulation
of MMP-2 and MMP-9 expressions in LNCaP and DU-145 prostate
cancer cells [44]. In gastric cancer, xenograft angiogenesis and
tumor growth in BGC-823 cells were inhibited by a combination
of EGCG and docetaxel [40] or a mixture of EGCG and capecitabine
[38]. EGCG and ascorbic acid combination strongly suppressed pro-
liferation and metastasis through scavenging of reactive oxygen
species in SMMC-7721 hepatocellular carcinoma [136]. EGCG (in
green tea extract), ascorbic acid, lysine, proline and arginine mix-
ture inhibited critical steps of cancer development and spread,
such as MMP-2 and -9 secretions and invasion in T-24 bladder can-
cer cells [137].
In CSCs, EGCG was also found to inhibit migration and invasion,
for example, it inhibited growth, spheroid formation, migration
and invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP,
Vimentin, Slug, Snail and nuclear b-Catenin in PC-3 and LNCaP
CSCs [132]. In addition, EGCG inhibited self-renewal and migration
and reversed the epithelial–mesenchymal transition via NF-
j
B p65
inactivation in nasopharyngeal CNE2 and C666-1 CSCs [138].
Anticancer effects of EGCG combined with nanoparticls
On the other hand, nanotechnology mediated approaches to
develop drugs have attracted intense attention in cancer preven-
tion and therapy research. Nanoparticles appears to hold great pro-
mise in the field of cancer management because of its unique
physicochemical properties including nanometer size, large sur-
face area-to-mass ratio, and efficient interaction with cells [2]. Sid-
diqui et al envisioned that nanoparticle-mediated delivery could be
useful to control the toxicity and enhance the bioavailability of the
chemopreventive agents such as EGCG, and introduced the concept
of ‘‘nanochemoprevention”[26,49,139,140]. These studies demon-
strated that EGCG encapsulated in polymeric nanoparticles (NPs)
exhibited over ten-fold dose advantage for exerting its apoptotic
and effects against cancer, both in vitro and in vivo [26,49].In
breast cancer, EGCG-Ptx-PLGA-Casein-NPs induce apoptosis in
MDA-MB-231 cells through inhibiting NF-
j
B activation [141].
EGCG-LDH nanohybrids induce apoptosis within over 5-fold dose
advantages in vitro compared to EGCG alone in prostate PC-3 can-
cer cells [142]. Similarly in PC-3, EGCG-PLA-PEG-NPs enhance
bioavailability and limited unwanted toxicity of EGCG within 10-
fold dose advantage [13] and induce apoptosis within remarkably
significant increase in pro-apoptotic Bax with a concomitant
decrease in anti-apoptotic Bcl-2 (Fig. 5), increase in poly(ADP-
ribose) polymerase (PARP) cleavage and marked induction of p21
and p27 [26].In vivo oral administration of EGCG-CS-NPs induces
apoptosis in 22R
m
1 prostate cancer cells increasing in Bax expres-
sion with a concomitant decrease in Bcl-2 and activation of cas-
pases [143]. Another study demonstrated apoptosis induction
(Bax, PARP) in tumors harvested from the treated mice within 8-
fold dose advantage of nanoformulation over native EGCG [144].
EGCG and HDHA-DOX-NPs combination induces apoptosis in Ehr-
lich’s ascites carcinoma (EAC) whereas EGCG enhances the anti-
cancer activities of HDHA-NPs significantly increasing the mean
survival time of the animals [145].In vitro treatment of 20
l
Mof
EGCG-PLGA-PEG-DCL-NPs or EGCG-PLGA-PEG-AG-NPs into PC-3,
LNCaP and DU-145 prostate cancer cells induces apoptosis upreg-
ulating Bax, DR5, and P27 and decreasing Bcl2 and survivin [89].
Moreover, EGCG-PLA-PEG-NPs inhibit proliferation in PC-3
prostate cancer cells through upregulation of p21 and p27 [26].
Finally, EGCG-NPs inhibit cell proliferation through cell cycle regu-
latory proteins via downregulation of Cyclin A, Cyclin B1, Cyclin D3,
surviving, CDK2 and CDK6 and upregulation of P21 and P27 [49].
EGCG-NPs was also found to inhibit cancer angiogenesis and
metastasis such as EGCG-Ptx-PLGA-Casein-NPs which downregu-
lated the key genes associated with angiogenesis, tumor metastasis
and survival as well as induced apoptosis and inhibited NF-
j
B acti-
vation in MDA-MB-231 breast cancer cells [141].
Conclusion
Chemoprevention, also defined as ‘‘slowing the process of car-
cinogenesis’’ concept appears to be a viable option for cancer con-
trol. To be effective, chemopreventive intervention should be
addressed during the early stages of the carcinogenesis process.
A plethora of experimental evidences suggest that both dietary
and lifestyle factors act by balancing promotion/prevention of
chronic inflammation and/or oxidative stress, sometime leading
alterations associated with cancer initiation. Within the chemopre-
ventive armamentarium, the use of natural agents from dietary
sources is generally preferred with respect to bioactive molecules
deriving from other sources. Many of these natural occurring
agents demonstrated antioxidant activity, and compounds belong-
ing to polyphenols chemical class may play a promising role for
cancer prevention. Epidemiological studies conducted in humans
support the existence of an association between natural polyphe-
nols consumption and a reduced cancer risk. In the last decade, a
representative member of polyphenols, i.e. EGCG, has been the
focus of a number of studies scrutinizing its beneficial effects on
health. Therefore, consumption of green tea has become more
and more popular in the world due to its versatile health benefits
[29]. Moreover, interesting preclinical evidence and encouraging
initial clinical trials have been obtained testing EGCG as chemopre-
ventive agent. However, despite its beneficial therapeutic poten-
tial, EGCG presents important pharmacokinetics problems, due to
inefficient systemic delivery and bioavailability. In order to
improve the poor systemic bioavailability and cellular uptake of
EGCG, various strategies have been adopted, which include combi-
nation therapy or polytherapy that consumes EGCG with one or
more medications. In particular, nanotechnology approaches could
help overcome pharmacokinetics issues of EGCG by controlling its
toxicity and enhancing its bioavailability to introduce the concept
of ‘‘nanochemoprevention”[26,49,139,140]. In addition, recent
studies conducted implying both EGCG and CSCs to found that
EGCG induces multiple of anticancer effects in CSCs and enhances
the chemo-sensitivity of chemo-drugs in CSCs.
In this review the current available studies of the anti-cancer
effects of EGCG alone and combined with other dietary and phar-
maceutical agents as well as the recent novel nanotechnology
approaches used to deliver sustained levels of EGCG have been
covered and discussed in order to introduce some furnish driving
force for further evolution of research on innovative database able
to consolidate the chemopreventive potential of EGCG.
Acknowledgements
The authors acknowledge support from Egyptian Ministry for
Higher Education for a fellowship to IR. IAS was supported by
Mentored Research Scholar Grant (MRSG-11-019-01-CNE) from
I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 19
the American Cancer Society. While preparing this review article
the core resources of P30AR066524 were used.
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