Egyptian Journal of Basic and Applied Sciences

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Cancer preventive and therapeutic effects of

EGCG, the major polyphenol in green tea

Islam Rady, Hadir Mohamed, Mohamad Rady, Imtiaz A. Siddiqui & Hasan
Mukhtar

To cite this article: Islam Rady, Hadir Mohamed, Mohamad Rady, Imtiaz A. Siddiqui & Hasan
Mukhtar (2018) Cancer preventive and therapeutic effects of EGCG, the major polyphenol in green
tea, Egyptian Journal of Basic and Applied Sciences, 5:1, 1-23, DOI: 10.1016/j.ejbas.2017.12.001

To link to this article: https://doi.org/10.1016/j.ejbas.2017.12.001

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 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

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

a r t i c l e i n f o a b s t r a c t

Article history: (-)-epigallocatechin-3-gallate (EGCG), the major bioactive catechin in green tea (GT) has been studied for
Received 14 November 2017 almost past thirty years as an agent initially for its cancer chemoprevention effects and then for its cancer
Accepted 6 December 2017 chemotherapeutic ability. This agent has shown considerable anti-cancer effects in a variety of preclinical
Available online 19 December 2017
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
Keywords: studies assessing the effects derived from the use of EGCG are been employed in combination with other
Green tea
agents or by utilizing innovative carrier settings. Here, we summarize the current understanding of the
EGCG
Anti-cancer effects
anticancer effects of EGCG and its effects with other combinations on different kinds of cancers.
Cancer nanochemoprevention Further, we also present the available information for the possible mechanism of action of EGCG.
Ó 2017 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 as one of the leading causes of mortality worldwide, for instance,

above 10 million new patients are diagnosed with cancer every
Cancer is a group of diseases involving abnormal cell growth year and over 6 million deaths are associated with it representing
with the potential to invade or spread to other parts of the body roughly 12% of worldwide deaths [2]. Almost fifteen million new
[1]. It is one of the major ailment effecting humankind and remains 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-
⇑ Corresponding author at: Department of Dermatology, University of Wisconsin-
Madison, Medical Sciences Center, #B-25, 1300 University Avenue, Madison, WI
lation might be increase the new cancer cases to 21.7 million
53706, USA. within about 13 million cancer deaths by the year 2030 [5]. The
E-mail address: [email protected] (H. Mukhtar). development of cancer is a multifactorial process [6] which can

https://doi.org/10.1016/j.ejbas.2017.12.001
2314-808X/Ó 2017 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/).
2 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

Fig. 1. Schematic drawing of green tea leaves composition.

be caused by external factors such as infectious organisms, envi- Tea catechins were first isolated by Michiyo Tsujimura in 1929
ronmental pollutants, tobacco and an unhealthy diet or internal in Japan [16] and since then four main types of catechins have been
factors such as hormones, inherited genetic mutations and found in green tea leaves (Table 1): (-)-epigallocatechin-3-gallate
immune conditions may act together or singular to cause the incip- (EGCG) accounts for approximately 59% of the total catechins from
ience of cancer [7]. Since cancer is associated with such high mor- the leaves of the green tea, (-)-epigallocatechin (EGC) (19%), (-)-
bidity and mortality worldwide, there is an urgent need to epicatechin-3-gallate (ECG) (13.6%), and (-)-epicatechin (EC)
determine ways of management of this ailment where the current (6.4%) [17,18]. The functional and structural differences between
treatment modalities are mainly surgery, radiation based therapy, these catechins are attributed to the number of hydroxyl groups
chemotherapy, gene therapy and/or hormonal therapy [2]. Natural on the B-ring (Fig. 2) and the presence or absence of a galloyl moi-
products, especially those derived from plants, have been used to ety [18].
help mankind sustain its health since the dawn of medicine [8]. Among these catechins, EGCG is the most studied and is consid-
Nowadays, just like in ancient times, natural compounds are still ered to play a crucial role in cancer-preventive and therapeutic
determining factors in remedies [9]. activities [19–23]. Several studies have been performed to examine
Herbal medicine or Herbalism (also known as phytotherapy) is the effects of EGCG on various in vitro cancer-related molecular
the study of botany and use of plants intended for medicinal pur- targets and in vivo models for potential cancer chemoprevention
poses or for supplementing a diet, has been applied for thousands and therapy [24]. The overwhelming majority of these studies
of years, but researchers started to study their mode of action at observed that EGCG inhibits a vast array of anticancer molecular
the molecular, cellular and tissue levels only recently [10–12]. It targets (Fig. 3) and cancer-related cellular processes [25].
is also a firm belief that naturally occurring plant based natural Despite accomplished outcomes in preclinical settings, its appli-
compounds when properly formulated and administered have a cability to humans has met with limited success for many reasons
key role in cancer management. including inefficient systemic delivery and bioavailability. Several
Chemoprevention, especially through the use of naturally optimization approaches including utilization of nanoparticle
occurring phytochemicals capable of impeding the process of car- based delivery of EGCG have been utilized to circumvent the issues,
cinogenesis at one or more steps, is an ideal approach for cancer for instance, we in a seminal study [26] introduced the novel con-
management [13]. Among natural compounds, ever since our ini- cept of ‘‘nanochemoprevention” that utilizes nanotechnology for
tial work in describing its potential benefit against cancer, green enhancing the outcome of EGCG in cancer chemoprevention.
tea has been extensively studied worldwide in a variety of cancer Combination therapy or polytherapy (versus monotherapy) is
models and the resulting data has been very promising. Green therapy that consumes more than one medication. There has been
tea leaves comprises of a diverse number of components (Fig. 1) some emphasis on determining the effects of combining EGCG
that are demonstrated to be beneficial to human health. The green with other dietary agents. Several studies have indicated that
tea polyphenols are flavonols, commonly known as catechins [14] anti-cancer efficacy and scope of action of the individual agents
which are found in greater amounts in green tea than in black or can be further enhanced by combining them synergistically
Oolong tea [15]. with chemically similar or different compounds (Fig. 4). Such a
 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 3

Table 1
Dried green tea composition.

Molecular group Component Molecular MW Percent of dried Main Biological effects

Formula (g/mol) tea extract
Polyphenols Epicatechin C15H14O6 290.26 30–42 Cancer prevention, antioxidant, antibacterial and
Epicatechin-3-gallate C22H18O10 442.37 antiviral effects.
Catechins Epigallocatechin C15H14O7 306.27
Epigallocatechin-3- C22H18O11 458.375
gallate (EGCG)
Kaempferol C15H10O6 286.23 5–10 Anti-histamine and anti-inflammatory effects.
Flavonols Quercetin C15H10O7 302.236
Myricetin C15H10O8 318.2351
Theogallin C14H16O10 344.27 2–4 Inhibition of Influenza A viruses.
Depsides Chlorogenic acid C16H18O9 354.31
Coumarylquinic acid C16H18O8 338.312
Organic acids Ascorbic acid C6H8O6 176.124 1–2 Anticancer effects.
Gallic acid C7H6O5 170.12 0.5
Quinic acid C7H12O6 192.17 2
Folic acid C19H19N7O6 441.404 0.5
Other organic acids – – 4–5
Amino acids Theanine C7H14N2O3 174.2 4–6 Neuronal cell protection and relaxation effect.
c-aminobutyric acid C4H9NO2 103.121 2–4 Decrease of blood pressure.
Methylxanthines Caffeine C8H10N4O2 194.19 7–10 Increased alertness and a mild diuretic effects.
Theobromine C7H8N4O2 180.164
Theophylline C7H8N4O2 180.167
Carbohydrates Glycosides – – 10–15 Energy and prevent blood sugar increase.
Minerals Aluminium, fluorine, manganese, iron, – – 6–8 Regulators.
magnesium, potassium, phosphorus,
zinc, selenium and sodium.
Volatiles Saponin C58H94O27 1223.363 0.02–1 Anti-fungal, anti-inflammatory, and anti-allergy
Linalool C10H18O 154.25 properties.
4-Cardinene C15H24 204.357
Geraniol C10H18O 154.253
Nerolidol C15H26O 222.37
a-Terpineol C10H18O 154.25
Cis-Jasmone C11H16O 164.246
Indole C8H7N 117.15
b-Inone C13H20O 192.302
1-Octanal C8H16O 128.215
Indole-3-Carbinol C9H9NO 147.18
b-Caryophyllene C15H24 204.36
Vitamins Thiamine (B1) C12H17N4OS+ 265.355 – Maintenance of healthy skin and mucus membrane.
Riboflavin (B2) C17H20N4O6 376.369
Niacin (B3) C6H5NO2 123.111
Vitamin B6 C8H11NO3 169.18
Vitamin E C29H50O2 430.717
b-Carotene C40H56 536.888
Chlorophyll – C55H72O5N4Mg 893.509 – Deodorizing effect, kidney stone prevention and
strengthens immune system.

combination might be effective in reducing the drug dosage and EGCG anticancer effects
resistance, and simultaneously exhibiting higher therapeutic out-
come [27–29]. Studies suggest that EGCG can synergistically inhi- Induction of apoptosis
bit cancer cells in vitro and in vivo when combined with other
dietary agents (Table 2), such as [6]-gingerol [30], curcumin [31], Apoptosis is a genetically encoded program leading to cell death
lovastatin [32], quercetin [33], sulforaphane [34], panaxadiol that is involved in normal development and homeostasis through-
[35], and pterostilbene [36]. Some evidence is also available for out the animal kingdom [50]. It is the main event that is known to
combination with chemotherapeutic agents such as 5- regulate the occurrence and/or spread of cancer [2]. The morpho-
fluorouracil [37], capecitabine [38], cisplatin [39], docetaxel [40], logical characteristicsof apoptosis include cell shrinkage, nuclear
doxorubicin [41] and temozolomide [42], or other agents like fragmentation, chromatin condensation and membrane blebbing
sodium butyrate [43], vitamin C and amino acids [44]. Combina- [50–52]. Apoptosis can undertake one or two pathways, intrinsic
tion of EGCG with these molecules can synergistically inhibit can- and/or extrinsic pathway (s) [53]. Intrinsic pathway, also known
cer cell proliferation [45,46], induce apoptosis [47,48] and suppress as mitochondrial pathway, can be induced through intracellular
tumor angiogenesis and growth [40] to name a few pathways that stresses via DNA damage or oxidative stress leading to release of
are effected by such an amalgamation. This synergistic effect, on mitochondrial Cytochrome C to form apoptosome complex [54].
one hand, may be associated with enhanced bioavailability of This complex is composed of Cytochrome C, apoptotic protease
EGCG [49]. Studies find that natural small molecules, such as quer- activating factor 1 (Apaf-1) and procaspase-9 [55], which activates
cetin can increase the bioavailability of EGCG in vitro and in vivo Caspase-9, Caspase-3 and Caspase-7 [56]. Otherwise, extrinsic
[33]. Current literature summarize the current understanding of pathway or death receptor pathway can be induced by death
the anti-cancer effects of EGCG alone and in combination with ligands Fas ligand (FasL), tumor necrosis factor a (TNFa) and
other dietary and pharmaceutical agents. TNF-related apoptosis inducing ligand (TRAIL) [57]. These ligands
4 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

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
Fig. 2. Molecular structure green tea catechins.
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
bind to their cell surface receptors TNFR1 and TNFR2, death recep- cells trough gene expression regulation [85,88]. Moreover, EGCG
tor DR4 and DR5 and Fas causing sequential activation of Caspase- also suppresses cyclin D1 and activate p21 via ERK, IKK and PI3K
8, Caspase-3 and Caspase-7 [58]. Moreover, apoptosis is regulated signaling pathway in order to inhibit cell proliferation in HCT-
by several proteins such as BCL-2 [59], BAX [60], BCL-XL [61], BCL- 116, Caco-2, HT-29 and SW480 colorectal cancer cells [89]. EGCG
XS [62] BAD [63], BAK [64], BID [65], BIM [66], PUMA [67], XIAP also induces cell cycle arrest in A431 skin cancer cells through inhi-
[68], NOXA [69], SMAC [70], MCL-1 [71] and c-FLIP [72]. bition of Cip1/p21 without any changes in Kip1/p27, CDK2, and
EGCG induced cell apoptosis (Table 3) through intrinsic mito- cyclin D1 while there was a decrease in CDK4 only at low doses
chondrial pathway via activation of Caspase-9 in PC3 prostate can- [90,91].
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 Inhibition of angiogenesis and related mechanisms
also been shown to induce apoptosis through extrinsic death
receptor pathway in MIA-Pa-Ca-2 pancreatic cancer cells via acti- Like all cells, cancer cells require a constant supply of nutrients
vation of Fas, DR5 and Caspase-8 [74]. In addition, EGCG downreg- and oxygen in order to grow and divide [92], and thus without an
ulated the expression of anti-apoptotic proteins, such as BCL-2 in adequate blood supply cancers might not grow [93]. Angiogenesis
PANC-1, MIA-Pa-Ca-2, Hs 766 T and AsPC-1 pancreatic cancer cells is the physiological process through which new blood vessels form
[48], MDA-MB-231 breast cancer cells [75], NCI-H295 adrenal can- from pre-existing vessels [94]. Cancers induce angiogenesis by
cer cells [76] and PC-12 pheochromocytoma cells [77], BCL-XL in secreting various growth factors such as vascular endothelial
PANC-1, MIA-Pa-Ca-2, Hs 766 T and AsPC-1 cells pancreatic cancer growth factor (VEGF) which is the major contributor to angiogen-
cells [48] and NCI-H295 adrenal cancer cells [76], survivin in MCF- esis, increasing the number of capillaries in a given network [95].
7 breast cancer cells [73] and NUGC-3 gastric cancer cells [78]; and Inhibition of cancer angiogenesis is increasing the death of the
XIAP in NCI-H295 adrenal cancer cells [76]. Also, EGCG was found tumor tissue (necrosis) whereas the presence of tumor necrosis
to upregulate the expression of pro-apoptotic proteins, including within primary tumors is associated with angiogenesis responses
 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 5

Fig. 3. Schematic drawing of the regulative actions of EGCG. This carton is based on the available literature about the anticancer effects of EGCG.

[96–98]. Furthermore, cancer cell motility, migration and invasion cells, EGCG inhibited invasion, epithelial-mesenchymal transition,
play fundamental roles in cancer metastasis [99]. Therefore, and tumor growth through downregulation of MMP-2, uPA, p-
inhibiting either cancer cell motility, migration or invasion impede FAK, p-Src, snail-1 and vimentin [111]. EGCG inhibits HGF-
metastasis, which is the cause of over 90% of patient deaths [100]. induced cell growth and invasion through suppression of HGF/c-
EGCG has demonstrated potential efficacy in inhibiting angio- Met signaling pathway [112]. Repressing of functional invadopodia
genesis, necrosis, motility, invasion, migration and metastasis formation was done by EGCG to inhibit in vitro and in vivo invasion
markers in a variety of human cancers tested under preclinical in HSC-3 and YD-10B oral cancer cells FAK/Src signaling [113]. In
model systems. In A549 lung cancer cells, EGCG was observed to Hypopharyngeal FaDu and laryngeal SNU-899 and SNU-1066 can-
inhibit angiogenesis and reduce xenograft tumor growth through cer cells, EGCG Inhibited HGF-induced cell growth and invasion
inhibiting IGF-1 via suppressing HIF-1a and VEGF protein expres- through suppression of HGF/c-Met signaling pathway [112]. In gas-
sion [101–104], upregulation of endostatin expression [102], inhi- tric cancer, EGCG inhibited xenograft angiogenesis and tumor
bition of HPV-16 oncoprotein induced angiogenesis conferred by growth in BGC-823 [40]. EGCG inhibited IL-6-induced angiogenesis
cancer cells via inhibition of HIF-1a protein expression and HIF- in vitro and in vivo through inhibition of VEGF expression via sup-
1a dependent expression of VEGF, IL-8, and CD31 and activation pressing Stat3 activity in AGS cells [114]. In SGC-7901 cancer cells,
of Akt [104]. In addition, EGCG inhibits nicotine-induced migration, EGCG inhibited tumor growth and angiogenesis through reducing
invasion through upregulation of HIF-1a, VEGF, COX-2, p-Akt and VEGF-induced endothelial cell proliferation, migration and tube
p-ERK [105]. Similarly, in lung NCI-H460 cancer cells, EGCG Inhi- formation [115]. In squamous cell carcinoma, EGCG inhibited
bits angiogenesis through inhibition of HIF-1a protein expression HGF-induced cell growth and invasion through suppression of
and HIF-1a dependent expression of VEGF, IL-8, and CD31 as well HGF/c-Met signaling pathway in SCC VII/SF cells while it inhibited
as activation of Akt [104]. EGCG also was able to inhibit cell motil- xenograft tumor growth in vivo via rising apoptosis [112]. In hep-
ity in vitro wound healing assay in H1299 and Lu99 lung cancer atocellular carcinoma, in Hepa 1c1c7 cells, EGCG inhibited cell
cells [106]. In ovarian cancer, EGCG inhibited cell motility through motility via suppression of Hsp90 chaperone system [107]. In cer-
suppression of Hsp90 chaperone system in SKOV3 cells [107]. On vical cancer, EGCG inhibited cell proliferation, invasion and migra-
breast cancer, only 10 lM of EGCG was able to inhibit cell migra- tion in HeLa cells through downregulation of MMP-9 gene and
tion trough downregulation of VEGF expression in Hs578T breast upregulation of TIMP-1 gene [85]. In colorectal cancer, EGCG inhib-
[130]. In NF639 breast cancer cells, EGCG inhibited branching col- ited tumor growth in vitro in SW837 cells and in vivo and through
ony growth and cell invasion through induction of estrogen recep- activation of VEGF/VEGFR axis via suppressing the expression of
tor a expression via activating FOXO3a signaling [108]. EGCG HIF-1a and several major growth factors [116]. EGCG also inhib-
inhibits cell migration and invasion through downregulation of ited migration and proliferation in SW620 cells in vitro through
VASP expression and Rac1 activity [109] in MCF-7 cancer cells. inactivation of PAR2-AP and factor VIIa and by the way inhibition
EGCG also Inhibits cell invasion, motility and migration in MDA- of the ERK1/2 and NF-jB pathways [117]. Moreover, EGCG inhib-
MB-231 through inhibition of EGF-induced MMP-9 via suppressing ited inhibits liver metastasis in vivo RKO colorectal cancer cells
FAK and ERK signaling pathways [110]. In oral cancer, in SCC-9 experiments and suppresses angiogenesis and induces apoptosis
6 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

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.

in liver metastasis [118]. EGCG inhibited Met signaling which helps have been employed to induce apoptosis in different cancers. The
to attenuate tumor spread/metastasis, independent of H2O2- general idea is that combination of two or more agents could target
related mechanisms in HCT-116 and HT-29 colorectal cancer cells more pathways and thus will be more effective to increase the sta-
[119,120]. In bladder cancer, EGCG inhibited cell adhesion, migra- bility of the agent and reduce toxicity to simultaneously exhibit
tion and invasion in T-24 cells through downregulation of MMP-9 higher therapeutic outcome. Various studies found that EGCG syn-
expression via blocking of NF-jB signaling pathway [121]. In eso- ergistically induced cancer cells apoptosis in vitro and in vivo
phageal TE-8 and SKGT-4 cancer cells, EGCG reduced cell viability through different apoptotic signaling, upregulation of pro-
and invasion in vitro through reduction of p-ERK1/2, c-Jun and apoptotic proteins and inhibition of anti-apoptotic proteins when
COX-2, and activation of caspase-3 whereas it inhibits tumor combined with other natural molecules, such as vitexin-2-O-
growth in vivo through suppressing the expression of Ki67, p- xyloside and raphasatin [46], curcumin [125], N-acetylcysteine
ERK1/2 and COX-2 [32]. In prostate cancer, EGCG inhibited cell (NAC) [126], pterostilbene [36], tumor necrosis factor-related
motility and invasion through inhibition of c-Met signaling via apoptosis-inducing ligand (TRAIL) [74], quercetin [33], whole
altering the structure or function of lipid rafts in DU-145 cells green tea polyphenols (GTPs) [127], eicosapentaenoic acid-free
[122]. In addition, EGCG Inhibited tumor growth and angiogenesis fatty acid (EPA-FFA) and grape seed [GS] extract [128], 5-
in CWR22Rv1 cells but promoting apoptosis of the prostate cancer fluorouracil (5-FU) [37], sodium butyrate (NaB) [43] and [6]-
cells in vivo [123]. In BCaPT10 cancer cells, EGCG inhibited cell Gingerol and tocotrienol-rich fraction (TRF) [30].
motility in vitro via suppression of Hsp90 molecular chaperone sys- Combination of EGCG with curcumin induces apoptosis through
tem which supports malignant phenotype [124]. EGCG-P is more upregulation of caspase-dependent apoptotic signaling pathways
stable and effective than EGCG enhancing the inhibition of the in MCF-7 breast cancer cells [125]. However, a mixture of EGCG,
tumor growth, angiogenesis of CWR22Rv1 prostate cancer cells vitexin-2-O-xyloside and raphasatin was found to induce apoptosis
in vivo [123]. 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-20 -NAC adduct which induces cell cul-
Anticancer effects of EGCG combinations ture apoptosis in CL-13 lung cancer cells [126]. Also, pterostilbene
and EGCG combination induced apoptosis in both PANC-1 and
Induction of apoptosis MIA-Pa-Ca-2 pancreatic cancer cells [36] Adding TRAIL to EGCG
increases synergistically apoptosis induction via cleavage of
Several studies have stated that EGCG and its combinations procaspase-3 in MIA-Pa-Ca-2 cells [74]. Studies observed that nat-
have induced apoptosis in a variety of cancers. EGCG as a green ural small molecules, such as quercetin, can increase the bioavail-
tea polyphenol (GTP) or combined with different natural molecules ability of EGCG in rats and human [129] enhancing apoptosis
 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 7

Table 2
Compounds have previously combined with EGCG.

Molecular structure Molecular MW Cancers (cell lines)

Formula (g/mol)
[6]-Gingerol C17H26O4 294.391 Glioma (SW1783, LN18 and
1321N1) [30]

Arginine C6H14N4O2 174.204 Prostate (PC-3, LNCaP and

DU-145) [44] and bladder
(T-24) [137] cancers

Ascorbic acid C6H8O6 or 176.124

HC6H7O6

Curcumin C21H20O6 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 Epicatechin C15H14O6 290.26 Prostate (LNCaP) cancer
polyphenols (GTP) [147]

Epicatechin-3- C22H18O10 442.37

gallate

Epigallocatechin C15H14O7 306.27

Kaempferol C15H10O6 286.23

Quercetin C15H10O7 302.236 Prostate (PC-3 [33] and

LNCaP [33] [147]) cancer

Myricetin C15H10O8 318.2351 Prostate (LNCaP) cancer

[147]

(continued on next page)

(continued on next page)

8 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

Table 2 (continued)

Molecular structure Molecular MW Cancers (cell lines)

Formula (g/mol)
Theogallin C14H16O10 344.27

Chlorogenic acid C16H18O9 354.31

Coumarylquinic C16H18O8 338.312

acid

GS C31H28O12 592.553 Colorectal (HCT-116 and

SW480) cancer[128]

Polyphenon E Caffeine C8H10N4O2 194.194 Lung cancer [148]

(+)- C15H14O7 306.27

Gallocatechin

EGC

(+)-Catechin C15H14O6 290.271

EC
 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 9

Table 2 (continued)

Molecular structure Molecular MW Cancers (cell lines)

Formula (g/mol)
()- C22H18O11 458.375
Gallocatechin
gallate

ECG

()-Catechin C22H18O10 442.376

gallate

EGCG

pterostilbene C16H16O3 256.301 Pancreatic (PANC-1 and

MIA-Pa-Ca-2) cancer [36]

Sulforaphane C6H11NOS2 177.28 Prostate (PC-3) cancer [34]

Tocotrienol-rich fraction (TRF) C28H42O2 410.642 Glioma (1321N1, LN18 and

SW1783) [30]

TRAIL – – – Pancreatic (MIA-Pa-Ca-2)

cancer [74]

induced against cancer cells due to EGCG treatment, such as in Gingerol or EGCG and TRF combinations both can induce apoptosis
LNCaP and PC-3 prostate cancer cells [33]. In vivo GTPs (including in 1321N1, LN18 and SW1783 glioma cells through activation of
that contains EGCG) oral infusion resulted in significant apoptosis caspase-3 [30].
of cancer cells causing inhibition of prostate cancer development, On the other hand, cancer stem cells (CSCs) have been identified
progression, and metastasis [127]. A combination of EGCG, eicos- in a number of solid tumors, including breast cancer, brain tumors,
apentaenoic acid-free fatty acid and grape seed extract [128] or a lung cancer, colon cancer, and melanoma [130]. CSCs have the
mixture of EGCG and Fluorouracil (5-FU) [37] induced apoptosis capacity to self-renew, to give rise to progeny that are different
in both HCT-116 and SW480 colorectal cancer cells [37,128]. Also from them, and to utilize common signaling pathways [130,131].
apoptosis through survivin downregulation has been noted when CSCs may be the source of all the tumor cells present in a malig-
HCT-116, HT-29 and RKO colorectal cancer cells are treated with nant tumor, the reason for the resistance to the chemotherapeutic
a combination of EGCG and NaB [43]. Finally, both EGCG and [6]- agent used to treat the malignant tumor, and the source of cells
Table 3

10
Anticancer effects of EGCG alone and combination.

Cancers Cell lines EGCG Combination Dose & IC50 Biological effects
Breast cancer MDA-MB-231 EGCG 50 and 100 lM [149]; 50 and 80 lg/ Inhibits cell proliferation and viability through suppression of Wnt signaling via inducing the HBP1
mL [75]; 20, 40 and 60 lM [150]; 10 transcriptional repressor [149], epigenetic repression of hTERT [150] and inhibition of glucose
and 20 lM [110]; 0.01–1000 lM uptake and metabolism [151]. Induces cell apoptosis through stimulation of pro-apoptotic
[151]. signaling and downregulation of MMP-9 expression [75]. Inhibits cell invasion, motility and
IC50: 50 lM (24 h) [149], 15.7 lM migration through inhibition of EGF-induced MMP-9 via suppressing FAK and ERK signaling
[151] pathways [110].
pEGCG 20 lM [150]; 50 lmol/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 lM) and/or C Inhibits cancer proliferation in vitro and in xenograft mouse models through inhibition of VEGFR-1,
(2,3,4 and 6 lM) EGFR and AKT protein level [31].
EGCG (E) + Vitexin-2-O- E (10,20,30,40,50 lg/mL),  Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
xyloside (X) + Raphasatin (30,50,80, 100,120 lg/mL) and/or G induces apoptosis [46].
(G) (5,10,15,30,50 lg/mL).

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
IC50: E (135 ± 16), X (158 ± 13), G (36
± 5) lg/mL
EGCG-Ptx-PLGA-Casein-NPs – Induce apoptosis, inhibite NF-jB activation and downregulate the key genes associated with
angiogenesis, tumor metastasis and survival [141].
EGCG-LbL-PSS/PAH-NPs 1 or 5 lM [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 Induces growth inhibition and apoptosis through surviving expression downregulation via
and 100 [109]; 1 and 10 lM [153]; suppressing AKT pathway and activation of caspase-9 [73]. Inhibits cell migration and invasion
20, 40 and 60 [150]; 0.01–1000 lM through downregulation of VASP expression and Rac1 activity [109]. Inhibits nicotine and
[151]; 10, 20 and 40 lM [154]; 0.1, 1, estradiol-induced cell proliferation via downregulation of a9-nicotinic acetylcholine receptor
10, 50 and 100 lM [146]. IC50: 50 lg/ signaling pathway [153]. Inhibits cell viability and proliferation through epigenetic repression of
mL [73,109]; 44.1 lM [151] 40 lM hTERT [150], inhibition of glucose uptake and metabolism [151], epigenetic downregulation of ER-
[154]; 19–20 lM [146] a via p38MAPK/CK2 activation [154] and activation of Cav3.2 channels via elicit of Ca2 + spike
[146].
pEGCG 20 lM [150] Inhibit cell proliferation via epigenetic repression of hTERT [150]
EGCG + Curcumin E (2, 4, 10, 20, 40, 100) lM + C 20 lM 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- E (10,20,30,40,50 lg/mL), X Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
xyloside (X) + Raphasatin (30,50,80, 100,120 lg/mL) and G induces apoptosis [46].
(G) (5,10,15,30,50 lg/mL); IC50: E (135 ±
16), X (158 ± 13), G (36 ± 5) lg/mL
Hs578T EGCG 10 lM Inhibits cell proliferation and migration trough downregulation of VEGF expression [155].
T47D EGCG 10, 20 and 40 lM. Inhibits cell proliferation trough epigenetic downregulation of ER-a via p38MAPK/CK2 activation
IC50: 40 lM [154].
NF639 EGCG 20, 40, 60 and 80 mg/mL [156]; 40 lg/ Inhibits Her-2/Neu signaling, proliferation, and transformed phenotype of the Cancer Cells [156].
mL [108] 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 Suppresses tumor growth in vivo by inhibiting tumor-associated macrophage infiltration and M2
11 polarization [157].
ALDH1+ in SUM-149 EGCG 20, 40, 80 and 120 lg/mL Inhibits growth of cancer stem cells in vitro and in vivo. Inhibits spheroid formation and induces
and SUM-190 stem apoptosis [133].
cells
CD44+/CD24 in MDA- EGCG 20, 30 and 40 lM Inhibits tumorsphere formation and reduces cancer stem cell population through downregulation
MB-231 and MDA-MB- of estrogen receptor-a36, EGFR, p-ERK1/2 and p-AKT [158].
436 stem cells
Lung Cancer A549 EGCG 40–300 lM, IC50: 265 ± 7.1 lM (24 h) Induces cell apoptosis through inhibition of FASN activity and EGFR signaling pathway [101].
in vitro and 40 mg/kg/week by IP Reduces xenograft tumor growth and angiogenesis in vivo [101,102]through inhibiting of oncogene
injection into BALB/c nude female and IGF-1via suppressing HIF-1a and VEGF protein expression [103,104]. Inhibits cell proliferation
mice for 33 days [101]. 50 and 100 through upregulation of endostatin expression and suppression of VEGF expression [102] and
lM in vitro and 0.05% in drinking suppressing of the expression of the cell death-inhibiting gene, Bcl-xL [161]. Inhibits cell growth
water into BALB/c nude male mice for through induction of G0/G1 cell cycle arrest via inhibiting EGFR/cyclin D1 signaling [86] and
21 days [102]. 1, 5, 10, 20 and 40 lM upregulation of miR-210 expression via stabilizing HIF-1a [162]. Inhibits the anchorage-indepen-
[159]. 10, 25, 50 and 100 [104,105]. dent growth of cancer cells, induces p53 accumulation and upregulates its target genes, promotes
10–40 lM [86]. 80 lM [160]. 25 and the stability of p53 and MDM2, promotes nuclear localization and activity of p53, inhibits
100 [161]. 100 lM into flanks of nude proteasomal degradation-dependent p53 ubiquitination and inhibits the interaction of p53 and
mice [103–105]. 5,10,25 and 50 [162] 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-1a, VEGF, COX-2, p-Akt and p-ERK [105].
EGCG + Curcumin 10,20,40 lM EGCG and/or the same Inhibit cell growth in vitro and in vivo through induction of cell cycle arrest at G1 and S/G2 phases
concentrations for curcumin in vitro via downregulating cyclin D1 and cyclin B1 [45].
while fourteen 3 to 4-week old

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
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]
CL13 EGCG 5,10,25 and 50 Suppresses cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-
1a [162].
EGCG + N-acetylcysteine (0–100) lM of EGCG in the presence EGCG and NAC interact to form EGCG-20 -NAC adduct which induces cell culture apoptosis [126].
(NAC) or absence of 0–2 mM NAC.
H1299 EGCG 10,20,30,40 and 50 lM in vitro, 0.1, Inhibits cancer growth in vivo and in vitro and induces ROS and cell apoptosis [163]. Suppresses
0.3 and 0.5% in diets and 30 mg/kg/d cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1a [162].
by IP injection into male NCr nu/nu
mice for 45 days.
IC50: 20 lM in vitro and 0.15 lM
in vivo [163]; 5,10,25 and 50 [162]
H460 EGCG 1,5,10,20 and 40 lM [159]. 10–40 lM Inhibits the anchorage-independent growth of cancer cells, induces p53 accumulation and
[86]. 80 lM [160]. 5,10,25 and 50 upregulates its target genes, promotes the stability of p53 and MDM2, promotes nuclear
[162] 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-1a [162].
H1650 EGCG 1,5,10,20 and 40 lM [159]. 10–40 lM Inhibits the anchorage-independent growth of cancer cells, induces p53 accumulation and
[86] 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 lM [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].

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11
 12
Table 3 (continued)

Cancers Cell lines EGCG Combination Dose & IC50 Biological effects
H69 EGCG 20,40,50,60,80,100,120,140,150 and Induces cell apoptosis, reduces telomerase activity and inducts a cell-cycle block in S phase [164].
H69VP 200 lM. IC50: 70 lM (24 h)
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 lM EGCG and/or the same Inhibit cell growth in vitro and in vivo through induction of cell cycle arrest at G1 and S/G2 phases
concentrations for curcumin via downregulating cyclin D1 and cyclin B1 [45].
– EGCG + Polyphenon E Benzo(a)pyrene [B(a)P]-induced lung Mixture inhibits significantly pulmonary adenoma formation and growth in vivo [148].
cancer in female A/J mice (100 mg/
kg).
Pancreatic cancer AsPC-1 EGCG 5–80 lM [48] Induces apoptosis through cell cycle via G1 cell cycle arrest, regulation of cyclin D1, cdk4, cdk6, p21
Hs 766 T and p27, activation of ROS-mediated, p53-indepdendent apoptosis signaling, inhibition of Ras/Raf-
PANC-1 EGCG 5–80 lM [48] 1/ERK1/2 signaling, induction of MEKK1, JNK1/2 and p38 MAPK activities [48].
EGCG + Pterostilbene 20, 30 and 40 lM EGCG with/without The combination have additive, antiproliferative effects in vitro altering the apoptotic mechanisms
30 lM Pterostilbene by modulation at different points in the mechanism as well as the cell cycle arrest effect [36].

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
MIA-Pa-Ca-2 EGCG 10, 100 and 1000 lM, IC50 below 50 Induces apoptosis through cell cycle via G1 cell cycle arrest, regulation of cyclin D1, cdk4, cdk6, p21
lM [165]; 5–80 lM [48] 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 lg/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 lM EGCG with/without The combination have additive, antiproliferative effects in vitro altering the apoptotic mechanisms
30 lM Pterostilbene 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 lg/mL [166]; Inhibits cell proliferation and induces apoptosis through inhibition of cell cycle and DNA synthesis
20,40,60,80,100 and 120 lg/mL inducting NDA damage [166]. Downregulates AQP5, nuclear p65 and Ij-Ba expressions [167].
[167]; 100 lM [107] Inhibit cell motility via suppression of Hsp90 chaperone system [107].
Oral cancer SAS EGCG 20 and 40 lM [168] Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
Cal-27 via blocking the IFN-c-induced JAK-PKC-d-STAT1 signaling pathway [168].
Ca-922
SCC-9 EGCG 5,10,15 and 20 lM in vitro; 10 and 20 Inhibits invasion, epithelial-mesenchymal transition, and tumor growth through downregulation of
mg/day/kg by oral gavage into the MMP-2, uPA, p-FAK, p-Src, snail-1 and vimentin [111].
right front axilla of BALB/c nude mice
SCC-4 EGCG 20 and 40 lM [168]; 10, 20, 50, 100, Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
and 200 lM [169] 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 lM Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
pathway [112].
HSC-3 EGCG 20 and 40 lM [168]; 10,25,50 and Provides antitumor immunity through inhibition of indoleamide 2,3-dioxygenase (IDO) expression
100 lM [113] 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 lM in vitro; 20 mg/ Inhibits cancer invasion in vitro and in vivo via repressing functional invadopodia formation and
d/kg IP injection into the tongue of FAK/Src signaling [113].
male BALB/c athymic nude mice
every other day for 4 weeks
Hypopharyngeal FaDu EGCG 5,10,20,40,80,100,150 and 200 lM Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
cancer pathway [112].
Laryngeal cancer SNU-899 EGCG 5,10,20,40,80,100,150 and 200 lM Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
SNU-1066 pathway [112].
Nasopharyngeal (Oct4high/Nanoghigh/b- EGCG+Cisplatin (20 and 40 lM) E and/or (0.01, 0.1, 1 Mixture inhibits spheroid formation and cell viability as well as EGCG enhances chemo-sensitivity
cancer cateninhigh/ABCG2high/ and 10 lg/mL) C of cisplatin in vitro through downregulation of Oct4, b-Catenin, Nanog, ABCG2, MRP-1, MDR-1, p-
MRP-1high/MDR-1high) STAT3, Bcl-2, Survivin and c-Myc [170].
in TW01 CSCs
(Oct4high/Nanoghigh/b-
cateninhigh/ABCG2high/
MRP-1high/MDR-1high)
in TW06 CSCs
 CNE2 EGCG + Cisplatin EGCG (20 lM) + Cisplatin (10 lM) EGCG increases chemo-sensitivity of cisplatin in vivo [138].
were injected subcutaneously into
the flanks of nude mice and allowed
to grow for 8 weeks
CD44+ in CNE2 CSCs EGCG 25,50 and 75 lM Inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial–
mesenchymal transition via NF-jB p65 inactivation [138].
C666-1 EGCG + Cisplatin EGCG (20 lM) + Cisplatin (10 lM) EGCG increases chemo-sensitivity of cisplatin in vivo [138].
were injected subcutaneously into
the flanks of nude mice and allowed
to grow for 8 weeks
CD44+ in C666-1 CSCs EGCG 25,50 and 75 lM Inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial–
mesenchymal transition via NF-jB 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 Inhibits xenograft angiogenesis and tumor growth [38].
gavage + EGCG (IP injection of 1.5 mg
EGCG daily
AGS EGCG 5,10,25 and 50 lM in vitro and 50 lM Inhibits IL-6-induced angiogenesis in vitro and in vivo through inhibition of VEGF expression via

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
EGCG + AGS cells in vivo into BALB/c suppressing Stat3 activity [114]. Inhibits cell proliferation and induces cell apoptosis through
nude female mice for 7 days [114]; downregulation of Id1 expression [171].
20,40,60,80,120 and 240 lg/mL [171]
AZ521 EGCG 5,10,20 and 40 lM Inhibits cell proliferation through downregulation of DEAD-box RNA helicase p68 [172].
NUGC-3 EGCG 25,50,75 and 100 lM 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 Inhibit tumor growth and angiogenesis through reducing VEGF-induced endothelial cell
BALB/c nude for 28 days proliferation, migration and tube formation [115].
Hepatocellular Hepa 1c1c7 EGCG 100 lM Inhibit cell motility via suppression of Hsp90 chaperone system [107].
Carcinoma 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 lg) and EGCG (25 lmol) Combination significantly decreased the viability of cells, compared with EGCG or 5-FU-treated
cells [174].
CD133 and NANOG in EGCG 10 and 20 lM Inhibit sphere formation through inhibition of CD133, Nanog, ABCC1, ABCG2, Nek2 and p-Akt [174].
HepG2 cancer stem
cells
Squamous cell SCC VII/SF EGCG 5,10,20,40,80,100,150 and 200 lM Inhibits HGF-induced cell growth and invasion through suppression of HGF/c-Met signaling
carcinoma in vitro; 25,50 and 75 mg/kg/day IP pathway while it inhibits xenograft tumor growth in vivo via rising apoptosis [112].
injection into the flank of syngeneic
C3H/HeJ micefor 21 days
Prostate cancer PC-3 EGCG 0–50 lM. IC50 : 39.0 lM Antiproliferative effects through ERK1/2 activation via MEK-independent, PI3-K-dependent
signaling pathway [175].
1 and 25 lM. IC50: 25 lM Induces cell apoptosis through upregulation of caspase-9a expression [47].
EGCG + Curcumin 50 and 100 lM E and/or 50 lM C Induction of cell cycle arrest at both S and G2/M phases via upregulating p21 protein level [135].
EGCG + Quercetin 80 lM EGCG and/or 10 and 20 lM Mixture demonstrates enhanced inhibition of cell proliferation and induction of cell apoptosis
Quercetin in vitro by increasing the intracellular concentration of EGCG and decreasing EGCG methylation
[33].
EGCG + Sulforaphane 20 and 100 lM E and/or 25 lM S Reduction of cell viability via inhibition of AP-1 activation [34].
EGCG + Ascorbic acid + 50 microg/mL-500 lg/mL of the Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
Lysine + Proline + Arginine mixture 9 expressions [44].
EGCg-198AuNPs single-dose intra-tumoral 80% reduction of tumor volumes after 28 d demonstrating significant inhibition of tumor growth
administration in human prostate compared to controls [176].
cancer-bearing SCID mice
EGCG-LDH nanohybrids 25,50,75 and 100 lM/L; IC50: 16.66 Induce apoptosis within over 5-fold dose advantages compared to EGCG alone in in-vitro system
lM/L (24 h), 15.47 lM/L (48 h), [142].
16.33 lM/L (72 h)

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13
 14
Table 3 (continued)

Cancers Cell lines EGCG Combination Dose & IC50 Biological effects
EGCG-PLA-PEG-NPs 0.7,1.37,2.74 and 5.48 lmol/L in vitro, NPs enhance the bioavailability and limited unwanted toxicity of EGCG within 10-fold dose
IC50: 3.74 lmol/L (24 h); in vivo, mice advantage [13]. In addition, induce apoptosis within remarkably significant increase in pro-
each received 100 lg dissolved in PBS apoptotic Bax with a concomitant decrease in anti-apoptotic Bcl-2, increase in PARP cleavage and
thrice weekly [26] marked induction of p21 and p27 [26].
EGCG-PLGA-PEG-DCL-NPs 20 lM In vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
EGCG-PLGA-PEG-AG-NPs apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
PC-3ML EGCG + Doxorubicin 30 and 60 lM E + D in vitro; 0.14–57 Combination enhances the inhibition of metastatic tumor growth [41].
mg/kg E and/or 2 mol/L–0.07 mg/kg
D into immunodeficiency mice
(CD44+CD133+in PC-3) EGCG 30 and 60 lM Inhibits growth and spheroid formation, induces apoptosis, inhibits EMT, inhibits migration and
CSC invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP, Vimentin, Slug, Snail and nuclear b-
Catenin [132].
LNCaP EGCG 12 lM [177]; 20,40 and 80 lM [178]; Modulates cell growth, by affecting mitogenesis as well as inducing apoptosis, in cell-type-specific
10, 20, 40, and 80 lg/mL [87] manner which may be mediated by WAF1/p21-caused G0/G1-phase cell-cycle arrest, irrespective

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
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 10–80 lg/mL In vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase1
(GTP) [147].
EGCG + Quercetin 80 lM EGCG and/or 10 and 20 lM Quercetin enhances the anti-proliferative effects of EGCG and induction of cell apoptosis in vitro
Quercetin through increasing the intracellular concentration of EGCG and decreasing EGCG methylation [33].
EGCG + Ascorbic acid 50 microg/mL–500 lg/mL of the Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
+Lysine+Proline+Arginine mixture 9 expressions [44].
EGCG-PLGA-PEG-DCL-NPs 20 lM In vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
EGCG-PLGA-PEG-AG-NPs apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
(CD44+CD133+in EGCG 30 and 60 lM Inhibits growth and spheroid formation, induces apoptosis, inhibits EMT, inhibits migration and
LNCaP) CSCs invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP, Vimentin, Slug, Snail and nuclear b-
Catenin [132].
DU-145 EGCG 5 lM; 10, 20, 40, and 80 lg/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 + 50 microg/mL–500 lg/mL of the Combination inhibits cell proliferation and invasion through downregulation of MMP-2 and MMP-
Lysine + Proline + Arginine mixture 9 expressions [44].
EGCG-PLGA-PEG-DCL-NPs 20 lM In vitro, NPs enhance the anti-proliferative activity compared to the free EGCG modulating
EGCG-PLGA-PEG-AG-NPs apoptosis and cell-cycle. In vivo, NPs enhance the bioavailability and limited unwanted toxicity
[49].
CWR22R EGCG 50 mg/kg/d IP injection into nude Inhibits tumor growth and angiogenesis while promoting apoptosis of the prostate cancer cells
mice for 20 days. in vivo [123].
EGCG-P 86.7 mg/kg/d IP injection into nude EGCG-P is more stable and effective than EGCG enhancing the inhibition of the tumor growth,
mice for 20 days. angiogenesis and induces apoptosis of the prostate cancer cells in vivo [123].
BCaPT10 EGCG 2–200 lM in vitro; 0.06% in water Inhibits cell motility in vitro via suppression of Hsp90 molecular chaperone system which supports
into male athymic mice for 1 week malignant phenotype [124].
before xenograft surgery
BCaPM-T10 EGCG 0.06% in water into male athymic Inhibits a molecular chaperone supportive of the malignant phenotype [124].
mice for 1 week before xenograft
surgery
22Rm1 EGCG-CS-NPs 3 and 6 mg/kg by oral administration Inhibit AR-positive 22Rm1 tumor xenograft growth and secreted prostate-specific antigen levels
into athymic nude mice for 25 days 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 Inhibits cell proliferation and induces apoptosis through downregulation of AR, IGF-1, IGF-1R, p-
were fed AIN-76A diet and 0.06% ERK 1/2, COX-2, and iNOS [179].
EGCG in tap water for28 weeks
 – 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 lM in vitro; Induct apoptosis and cell cycle inhibition along with the growth of Mel 928 tumor xenograft.
IC50: 7 lM (48 h). 100 lg/mice;120 Inhibited proliferation (Ki-67 and PCNA) and induced apoptosis (Bax, PARP) in tumors harvested
lL treatment volume into Athymic from the treated mice within 8-fold dose advantage of nanoformulation over native EGCG [144].
(nu/nu) male nude mice.
Leukemia CEM (MSN@EGCG)-NPs 0.4, 0.8, 1.2 and 1.6 lM in vitro and Inhibit cell viability and proliferation in vitro and in vivo within a highly biocompatible and
100; NPS are i.v. injected into female biodegradable EGCG-coated MSN nanoparticles [180].
Balb/c mice
Cervical cancer HeLa EGCG 10, 25, 50 and 100 lM [88]; Cell growth inhibition trough gene expression regulation and induction of cell cycle arrest [88].
10,20,30,40,50,60,70,80,90 and 100 Inhibit cell proliferation, invasion and migration, and induce cell apoptosis through G1 cell cycle
lM [85]; IC50: 47.9 lM [88]; 100 lM arrest and DNA damage, downregulation of MMP-9 gene and upregulation of TIMP-1 gene [85].
(24 h) and 50 lM (48 h) [85].
CaSki EGCG 10, 25, 50 and 100 lM. IC50: 27.3 lM Cell growth inhibition trough gene expression regulation and induction of cell cycle arrest [88].
(24 h)
Colorectal cancer HCT-116 EGCG 0.05, 0.1, 0.5, 1, 5 and 10 lM [119]; Suppresses cancer cells growth through cyclin D1 degradation and p21 transcriptional activation
0.1, 0.5, 1, 5 and 10 lM [120]; 1, 10 via ERK, IKK and PI3K signaling pathway [89]. Inhibits Met signaling [119] which helps to attenuate

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
and 50 lM [89]; 50 and 100 lM tumor spread/metastasis, independent of H2O2-related mechanisms [120]. Inhibits cell prolifera-
[181]; 12.5,25,50 and 100 lM [118]. tion through inhibition of HGF-induced Met/ERK/AKT signaling pathway [119]and through
IC50: 3 lM [119] 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 lM) and/or P (0,10 Inhibit cell proliferation and induce cell cycle arrest [35].
and 20 lM)
EGCG + EPA-FFA + GS EGCG (0–175 lM) + EPA-FFA (0–150 Combination completely inhibited the mTOR signaling. Moreover, the treatment led to changes of
lM) + GS extract (0–15 lM) for 24 h 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 lg) and EGCG (25 lmol) Combination significantly decreased the viability of cells, compared with EGCG or 5-FU-treated
[174]; 25–400 lM of EGCG and/or cells [174] like the EGCG enhances 5-FU sensitivity and induces apoptosis in 5-FU resistant cancer
2.5–40 lM 5-FU [37]. cells [37].
EGCG + NaB 10 lM E +(1,2,3,4,5 and 6 mM) N. The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
IC50: 10 lM E + 5 mM N HDAC1, DNMT1, survivin and HDAC activity [43].
CD133 and NANOG in EGCG 10 and 20 lM Inhibit sphere formation through inhibition of CD133, Nanog, ABCC1, ABCG2, Nek2, and p-Akt
HCT-116 stem cells [174].
CD44, CD133 and EGCG 50, 100, 200 and 400 lM Induces apoptosis and cell cycle arrest, attenuate spheroid formation and enhance
ALDH1 in HCT-116 chemosensitivity of 5-FU in vivo [37].
stem cells
HCT-8 EGCG 10,20 and 35 lg/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 lM [183]; 1, 10 and 50 Induces cell growth inhibition as EGCG and 67LR at a physiological concentration can activate
lM [89] 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- E (10,20,30,40,50 lg/mL), X Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
xyloside (X) + Raphasatin (30,50,80, 100,120 lg/mL) and G induces apoptosis [46].
(G) (5,10,15,30,50 lg/mL);
IC50: E (135 ± 16), X (158 ± 13), G (36
± 5) lg/mL
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 lM [120]; 1, 10 Inhibits Met signaling and helps to attenuate tumor spread/metastasis, independent of H2O2-
and 50 lM [89]; 10,20 and 35 lg/mL related mechanisms [120]. Suppresses cancer cells growth through cyclin D1 degradation and p21
[182]; 5, 10 and 20 mg/kg/d oral transcriptional activation via ERK, IKK and PI3K signaling pathway [89]. Inhibits proliferation
gavage to male BALB nude mice for in vitro and in vivo and induces apoptosis and affectes the cell cycle of cancer cells via inhibiting of
28 days [185] or/14 days [182]. HES1 and Notch2 expressions [182]. Inhibit tumor growth and metastasis in vivo by upregulating
the Nrf2-UGT1A signaling [185].
EGCG + NaB 10 lM E + (1,2,3,4,5 and 6 mM) N. The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
IC50: 10 lM E + 5 mM N HDAC1, DNMT1, survivin and HDAC activity [43].

(continued on next page)

15
 16
Table 3 (continued)

Cancers Cell lines EGCG Combination Dose & IC50 Biological effects
SW837 EGCG 25 lg/mL in vitro; 0.01% and 0.1% in Inhibits tumor growth in vivo and in vitro through activation of VEGF/VEGFR axis via suppressing
drinking water to BALB/c nude mice the expression of HIF-1a and several major growth factors [116]. Provides antitumor
for 35 days [116]; 10,50 and 100 lM immunotherapy through inhibiting the expression and function of indoleamine 2,3–dioxygenase
[186] via suppression of STAT1 activation [186].
SW480 EGCG 1, 10 and 50 lM [89]; 10,20 and 35 Suppresses cancer cells growth through cyclin D1 degradation and p21 transcriptional activation
lg/mL [182] 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 lM) and/or P (0,10 Inhibit cell proliferation and induce cell cycle arrest [35].
and 20 lM)
EGCG + EPA-FFA + GS EGCG (0–175 lM) + EPA-FFA (0–150 Combination completely inhibits the mTOR signaling and lead to changes in protein translation of
lM) + GS extract (0–15 lM) for 24 h 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 lM of EGCG and/or 2.5–40 EGCG enhances 5-FU sensitivity and induces apoptosis in 5-FU resistant cancer cells [37]
lM 5-FU [37].

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
SW620 EGCG 25,50,75 and 100 lg/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-jB pathways [117].
LoVo EGCG 10,20 and 35 lg/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- E (10,20,30,40,50 lg/mL),  Mixture activates ROS mediated mitochondrial pathway causing G0/G1 cell cycle arrest and
xyloside (X) + Raphasatin (30,50,80, 100,120 lg/mL) and G induces apoptosis [46].
(G) (5,10,15,30,50 lg/mL); IC50: E (135 ±
16), X (158 ± 13), G (36 ± 5) lg/mL
RKO EGCG 12.5,25,50 and 100 lM in vitro; 30 Inhibits cell proliferation and induces cell apoptosis through inhibition of Akt, activation and
mg/kg IP injection to SCID male mice induction of p38 MAPK activation; inhibits liver metastasis in vivo and suppresses angiogenesis and
every other day for 2 weeks [118] induces apoptosis in liver metastasis [118].
EGCG + NaB 10 lM E + (1,2,3,4,5 and 6 mM) N. The combination treatment induces apoptosis and G2/M cell cycle arrest through decrease in
IC50: 10 lM E + 5 mM N 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- – Modify DNA damage in human lymphocytes from colon cancer patients and healthy individuals
glycolic acid])-NPs treated in vitro with platinum-based chemotherapeutic drugs [187].
Glioma 1321N1 EGCG 50,100,150,200,250 and 300 lg/mL; Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
IC50: 82.0 ± 10.31 lg/mL (24 h)
EGCG + [6]-Gingerol 50 lg/mL EGCG + GING; IC50: 40 ± Mixture inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
8.62 lg/mL
EGCG + Tocotrienol-rich 100 lg/mL EGCG + TRF; IC50: 100 ±
fraction (TRF) 9.5 lg/mL
LN18 EGCG 50,100,150,200,250 and 300 lg/mL; Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
IC50: 134.0 ± 11.36 lg/mL (24 h)
EGCG + [6]-Gingerol 50 lg/mL EGCG + GING; IC50: 24 ± Mixture inhibits proliferation and induces apoptosis through activation of caspase-3[30].
2.65 lg/mL
EGCG + Tocotrienol-rich 80 lg/mL EGCG + TRF; IC50: 88 ±
fraction (TRF) 11.14 lg/mL
SW1783 EGCG 50,100,150,200,250 and 300 lg/mL; Inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
IC50: 300.0 ± 9.10 lg/mL (24 h)
EGCG + [6]-Gingerol 60 lg/mL EGCG + GING; IC50: 60 ± Mixture inhibits proliferation and induces apoptosis through activation of caspase-3 [30].
5.6 lg/mL
EGCG + Tocotrienol-rich 100 lg/mL EGCG + TRF; IC50: 270 ±
fraction (TRF) 4.16 lg/mL
U87 EGCG + Temozolomide 100 lM E + 100 lM TMZ EGCG inhibits properties of glioma stem-like cells (CD133high/ALDH1high) and synergizes with TMZ
U251 through downregulation of P-glycoprotein inhibition [42].
SHG-44
C6
Skin cancer A431 EGCG 5, 10, 20, 40, and 80 lg/mL [90];100– Inhibits cell growth, viability and induces cell apoptosis [90,91] through inhibition of EGFR
200 lM [91]; 10,20,40 and 60 lg/mL signaling [91], inhibition of pRb-E2F/DP pathway [90], inducing cell cycle arrest [90,91], inhibition
[188] 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 lg/mL [188]; Reduces cell viability [188], induces cell apoptosis [188,189] and inhibits cell growth [189] through
10,20,40,60 and 100 lM [189] inactivation of b-catenin signaling [188] and influencing PcG-mediated epigenetic regulation of cell
cycle-related genes [189].
– Green tea polyphenols 200lL of a 5% solution Prevent the adverse effects of UV radiation in humans [190].
Esophageal cancer TE-8 EGCG 40 lM in vitro Reduces cell viability and invasion in vitro through reduction of p-ERK1/2, c-Jun and COX-2, and
EGCG (E) + Curcumin (C) E (40 lmol/L), C (40 lmol/L), and L (4 activation of caspase-3 whereas it inhibits tumor growth in vivo through suppressing the
EGCG (E) + Curcumin (C) + lmol/L) in vitro expression of Ki67, p-ERK1/2 and COX-2 [32].
Lovastatin (L)
SKGT-4 EGCG 40 lM in vitro and 50 lg/kg/d by oral
intake into nude mice for 30 days (5
day/week)
EGCG (E) + Curcumin (C) E (40 lmol/L), C (40 lmol/L), and L (4
EGCG (E) + Curcumin (C) + lmol/L) in vitro
Lovastatin (L)

I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23
Adrenal cancer NCI-H295 EGCG 10, 20, 30 and 40 mM in vitro; IC50: Induces cell apoptosis through activation of caspase-dependent, caspase-independent, the
20.34 mM (48 h) 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-jB signaling pathway [121].
EGCG (in green tea extract) 10,50,100,500 and 1000 mg/mL of the Mixture inhibits critical steps of cancer development and spread, such as MMP-2 and -9 secretions
+ Ascorbic acid + Lysine + mixture and invasion [137].
Proline + Arginine
Pheochromocytoma PC-12 EGCG 15 mg/kg IP injection into male BALB/ Inhibits tumor growth and induces cancer cell apoptosis via acetylation of amyloid precursor
c nude mice every other day for 15 protein [77].
days
Neuroblastoma (Nanoghigh/Oct4high/ EGCG 1,10,50 and 100 lM Inhibits the development of TICs in BE(2)-C cells as well as inhibits sphere formation and induces
ATP7Alow/DKK2low)in apoptosis [134].
BE(2)-C CSCs
Ehrlich’s ascites EAC EGCG + HDHA-DOX-NPs E (20 mg/kg b.wt., orally through EGCG enhances the anticancer activities of HDHA-NPs significantly increasing the mean survival
carcinoma gavage) + HDHA-DOX-NPs (1.5 mg/kg time of the animals and inducing apoptosis [145].
b.wt.) intravenously into Swiss albino
mice.
Head and neck K3 EGCG + Cisplatin 5,10,20 and 50 lM E and/or 5,10 and Inhibit sphere formation and CD44+ cell population; enhances chemosensitivity of cisplatin in vitro
squamous K4 20 lM C and in vivo through downregulation of Oct4, Sox2, ABCC2, ABCG2 and Notch1 [39].
carcinoma (HNSC) K5
CSCs

17
18 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

that give rise to distant metastases [130]. Recently, studies found mixture induces G0/G1 cell cycle arrest in MDA-MB-231 and MCF-
that EGCG can induce apoptosis to inhibit CSCs in vitro and 7 breast, Caco-2 and LoVo colorectal cancer cells [46]. EGCG and
in vivo. Besides, its effect of spheroid formation inhibition in CSCs, pterostilbene combination has antiproliferative effects in vitro as
it induces apoptosis, and enhances chemo-sensitivity of chemo- a cell cycle arrest induction in pancreatic PANC-1 and MIA-Pa-
drugs in CSCs, for instance, EGCG induces apoptosis through down- Ca-2 cancer cells [36]. Similarly, EGCG and panaxadiol mixture
regulating Casp3/7, Bcl-2, survivin and XIAP in PC-3 and LNCaP inhibit cell proliferation and induce cell cycle arrest in both HCT-
prostate CSCs [132]. In addition, EGCG treatment induced apopto- 116 and SW480 colorectal cancer cells [35]. EGCG, EPA-FFA and
sis in the breast SUM-149 and SUM-190 CSCs [133], colon HCT-116 GS combination blocks cell cycle in G0/G1 in both HCT-116 and
CSCs [37] and neuroblastoma BE(2)-C CSCs[134], and enhance the SW480 colorectal cancer cells [128]. EGCG and NaB combination
chemosensitivity of 5-FU in vivo [37]. treatment induces G2/M cell cycle arrest through decreasing sur-
vivin in HCT-116, HT-29 and RKO colorectal cancer cells [43]. Fur-
Modulation of cellular proliferation thermore, EGCG inhibit cell proliferation via induction of cell cycle
arrest and attenuate spheroid formation in colorectal HCT-116
On the other hand, EGCG and curcumin combination inhibits CSCs [37].
cell proliferation and growth in vitro and in vivo in lung A549
and NCI-H460 cancer cells through induction of cell cycle arrest Inhibition of angiogenesis and related mechanisms
at G1 and S/G2 phases via downregulating cyclin D1 and cyclin
B1 [45] while same combination induces cell cycle arrest at both EGCG combinations has also been observed to inhibit angiogen-
S and G2/M phases via upregulating p21 protein level in PC-3 pros- esis, necrosis, motility, invasion, migration and metastasis in
tate cancer cells [135]. EGCG, vitexin-2-O-xyloside and raphasatin 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.
 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23 19

in almost complete inhibition of distant site metastases in prostate cancer activities of HDHA-NPs significantly increasing the mean
cancer. Furthermore, GTP consumption caused significant apopto- survival time of the animals [145]. In vitro treatment of 20 lM of
sis of cancer cells causing inhibition of prostate cancer develop- EGCG-PLGA-PEG-DCL-NPs or EGCG-PLGA-PEG-AG-NPs into PC-3,
ment, progression, and metastasis [127]. A combination of EGCG LNCaP and DU-145 prostate cancer cells induces apoptosis upreg-
and curcumin or EGCG, curcumin and lovastatin was able to reduce ulating Bax, DR5, and P27 and decreasing Bcl2 and survivin [89].
cell viability and invasion in vitro in TE-8 and SKGT-4 esophageal Moreover, EGCG-PLA-PEG-NPs inhibit proliferation in PC-3
cancer cells through reduction of p-ERK1/2, c-Jun and COX-2, and prostate cancer cells through upregulation of p21 and p27 [26].
activation of caspase-3 whereas it inhibited tumor growth in vivo Finally, EGCG-NPs inhibit cell proliferation through cell cycle regu-
through suppressing the expression of Ki67, p-ERK1/2 and COX-2 latory proteins via downregulation of Cyclin A, Cyclin B1, Cyclin D3,
[32]. EGCG and doxorubicin mixture enhanced the inhibition of surviving, CDK2 and CDK6 and upregulation of P21 and P27 [49].
metastatic tumor growth in PC-3ML prostate cancer cells [41]. EGCG-NPs was also found to inhibit cancer angiogenesis and
EGCG, ascorbic acid, lysine, proline and arginine combination metastasis such as EGCG-Ptx-PLGA-Casein-NPs which downregu-
inhibited cell proliferation and invasion through downregulation lated the key genes associated with angiogenesis, tumor metastasis
of MMP-2 and MMP-9 expressions in LNCaP and DU-145 prostate and survival as well as induced apoptosis and inhibited NF-jB acti-
cancer cells [44]. In gastric cancer, xenograft angiogenesis and vation in MDA-MB-231 breast cancer cells [141].
tumor growth in BGC-823 cells were inhibited by a combination
of EGCG and docetaxel [40] or a mixture of EGCG and capecitabine Conclusion
[38]. EGCG and ascorbic acid combination strongly suppressed pro-
liferation and metastasis through scavenging of reactive oxygen Chemoprevention, also defined as ‘‘slowing the process of car-
species in SMMC-7721 hepatocellular carcinoma [136]. EGCG (in cinogenesis’’ concept appears to be a viable option for cancer con-
green tea extract), ascorbic acid, lysine, proline and arginine mix- trol. To be effective, chemopreventive intervention should be
ture inhibited critical steps of cancer development and spread, addressed during the early stages of the carcinogenesis process.
such as MMP-2 and -9 secretions and invasion in T-24 bladder can- A plethora of experimental evidences suggest that both dietary
cer cells [137]. and lifestyle factors act by balancing promotion/prevention of
In CSCs, EGCG was also found to inhibit migration and invasion, chronic inflammation and/or oxidative stress, sometime leading
for example, it inhibited growth, spheroid formation, migration alterations associated with cancer initiation. Within the chemopre-
and invasion and downregulates Casp3/7, Bcl-2, Survivin, XIAP, ventive armamentarium, the use of natural agents from dietary
Vimentin, Slug, Snail and nuclear b-Catenin in PC-3 and LNCaP sources is generally preferred with respect to bioactive molecules
CSCs [132]. In addition, EGCG inhibited self-renewal and migration deriving from other sources. Many of these natural occurring
and reversed the epithelial–mesenchymal transition via NF-jB p65 agents demonstrated antioxidant activity, and compounds belong-
inactivation in nasopharyngeal CNE2 and C666-1 CSCs [138]. 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-
Anticancer effects of EGCG combined with nanoparticls nols consumption and a reduced cancer risk. In the last decade, a
representative member of polyphenols, i.e. EGCG, has been the
On the other hand, nanotechnology mediated approaches to focus of a number of studies scrutinizing its beneficial effects on
develop drugs have attracted intense attention in cancer preven- health. Therefore, consumption of green tea has become more
tion and therapy research. Nanoparticles appears to hold great pro- and more popular in the world due to its versatile health benefits
mise in the field of cancer management because of its unique [29]. Moreover, interesting preclinical evidence and encouraging
physicochemical properties including nanometer size, large sur- initial clinical trials have been obtained testing EGCG as chemopre-
face area-to-mass ratio, and efficient interaction with cells [2]. Sid- ventive agent. However, despite its beneficial therapeutic poten-
diqui et al envisioned that nanoparticle-mediated delivery could be tial, EGCG presents important pharmacokinetics problems, due to
useful to control the toxicity and enhance the bioavailability of the inefficient systemic delivery and bioavailability. In order to
chemopreventive agents such as EGCG, and introduced the concept improve the poor systemic bioavailability and cellular uptake of
of ‘‘nanochemoprevention” [26,49,139,140]. These studies demon- EGCG, various strategies have been adopted, which include combi-
strated that EGCG encapsulated in polymeric nanoparticles (NPs) nation therapy or polytherapy that consumes EGCG with one or
exhibited over ten-fold dose advantage for exerting its apoptotic more medications. In particular, nanotechnology approaches could
and effects against cancer, both in vitro and in vivo [26,49]. In help overcome pharmacokinetics issues of EGCG by controlling its
breast cancer, EGCG-Ptx-PLGA-Casein-NPs induce apoptosis in toxicity and enhancing its bioavailability to introduce the concept
MDA-MB-231 cells through inhibiting NF-jB activation [141]. of ‘‘nanochemoprevention” [26,49,139,140]. In addition, recent
EGCG-LDH nanohybrids induce apoptosis within over 5-fold dose studies conducted implying both EGCG and CSCs to found that
advantages in vitro compared to EGCG alone in prostate PC-3 can- EGCG induces multiple of anticancer effects in CSCs and enhances
cer cells [142]. Similarly in PC-3, EGCG-PLA-PEG-NPs enhance the chemo-sensitivity of chemo-drugs in CSCs.
bioavailability and limited unwanted toxicity of EGCG within 10- In this review the current available studies of the anti-cancer
fold dose advantage [13] and induce apoptosis within remarkably effects of EGCG alone and combined with other dietary and phar-
significant increase in pro-apoptotic Bax with a concomitant maceutical agents as well as the recent novel nanotechnology
decrease in anti-apoptotic Bcl-2 (Fig. 5), increase in poly(ADP- approaches used to deliver sustained levels of EGCG have been
ribose) polymerase (PARP) cleavage and marked induction of p21 covered and discussed in order to introduce some furnish driving
and p27 [26]. In vivo oral administration of EGCG-CS-NPs induces force for further evolution of research on innovative database able
apoptosis in 22Rm1 prostate cancer cells increasing in Bax expres- to consolidate the chemopreventive potential of EGCG.
sion with a concomitant decrease in Bcl-2 and activation of cas-
pases [143]. Another study demonstrated apoptosis induction Acknowledgements
(Bax, PARP) in tumors harvested from the treated mice within 8-
fold dose advantage of nanoformulation over native EGCG [144]. The authors acknowledge support from Egyptian Ministry for
EGCG and HDHA-DOX-NPs combination induces apoptosis in Ehr- Higher Education for a fellowship to IR. IAS was supported by
lich’s ascites carcinoma (EAC) whereas EGCG enhances the anti- Mentored Research Scholar Grant (MRSG-11-019-01-CNE) from
20 I. Rady et al. / Egyptian Journal of Basic and Applied Sciences 5 (2018) 1–23

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