Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]-gingerol in cancer

Abstract

Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic, and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective / therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance, and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro / in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and
pathways of cell signaling, including Bax / Bcl2, p38 / MAPK, Nrf2, p65 / NF-Kβ, TNF-α, ERK1 / 2, SAPK / JNK, ROS / NFKβ / COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti-inflammatory activities.

Full text

REVIEW
Protective and therapeutic potential of ginger (Zingiber
officinale) extract and [6]‐gingerol in cancer: A comprehensive
review
Rosália Maria Tôrres de Lima
1,2
|Antonielly Campinho dos Reis
2
|
Ag‐Anne Pereira Melo de Menezes
1,2
|José Victor de Oliveira Santos
2
|
José Williams Gomes de Oliveira Filho
1,2
|José Roberto de Oliveira Ferreira
3
|
Marcus Vinícius Oliveira Barros de Alencar
1,2
|Ana Maria Oliveira Ferreira da Mata
1,2
|
Ishaq N. Khan
4
|Amirul Islam
5
|Shaikh Jamal Uddin
5
|Eunüs S. Ali
6
|
Muhammad Torequl Islam
7,8
|Swati Tripathi
9
|Siddhartha Kumar Mishra
10
|
Mohammad S. Mubarak
11
|Ana Amélia de Carvalho Melo‐Cavalcante
1,2
1
Northeast Biotechnology Network (RENORBIO), Postgraduate Program in Biotechnology, Federal University of Piauí, Teresina, Brazil
2
Laboratory of Genetical Toxicology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
3
Laboratory of Experimental Cancerology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
4
Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
5
Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, Bangladesh
6
Gaco Pharmaceuticals and Research Laboratory, Dhaka‐1000, Bangladesh; College of Medicine and Public Health, Flinders University, Bedford Park, Australia
7
Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam
8
Faculty of Pha rmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam
9
Amity Institute of Microbial Technology, Amity University, Noida, India
10
Cancer Biology Laboratory, School of Biological Sciences (Zoology), Dr. Harisingh Gour Central University, Sagar, India
11
Department of Chemistry, The University of Jordan, Amman, Jordan
Correspondence
Muhammad Torequl Islam, Department for
Management of Science and Technology
Development, & Faculty of Pharmacy, Ton
Duc Thang Universit y, Ho Chi Minh City,
Vietnam.
Email: muhammad.torequl.islam@tdt.edu.vn
Mohammad S. Mubarak, Department of
Chemistry, The University of Jordan, Amman
11942, Jordan.
Email: mmubarak@ju.edu.jo
Present Address
Eunüs S. Ali, Department of Biochemistry and
Molecular Genetics, Northwestern University
Feinberg School of Medicine, 320 E Superior
St, Chicago, IL 60611, USA.
Natural dietary agents have attracted considerable attention due to their role in pro-
moting health and reducing the risk of diseases including cancer. Ginger, one of the
most ancient known spices, contains bioactive compounds with several health benefits.
[6]‐Gingerol constitutes the most pharmacologically active among such compounds.
The aim of the present work was to review the literature pertaining to the use of ginger
extract and [6]‐gingerol against tumorigenic and oxidative and inflammatory processes
associated with cancer, along with the underlying mechanisms of action involved in
signaling pathways. This will shed some light on the protective or therapeutic role of
ginger derivatives in oxidative and inflammatory regulations during metabolic distur-
bance and on the antiproliferative and anticancer properties. Data collected from
experimental (in vitro or in vivo) and clinical studies discussed in this review indicate
that ginger extract and [6]‐gingerol exert their action through important mediators and
pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF‐κB, TNF‐α,
ERK1/2, SAPK/JNK, ROS/NF‐κB/COX‐2, caspases‐3, ‐9, and p53. This suggests that
Received: 2 February 2018 Revised: 31 May 2018 Accepted: 5 June 2018
DOI: 10.1002/ptr.6134
Phytotherapy Research. 2018;1–23. © 2018 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/ptr 1

ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant
antiproliferative, antitumor, invasive, and anti‐inflammatory activities.
KEYWORDS
[6]‐gingerol, anticancer activity, ginger extract, mechanism of action
1|INTRODUCTION
Cancer continues to be a global burden, despite the advent of various
technological and pharmaceutical improvements over the past two
decades (Seyed, Jantan, Bukhari, & Vijayaraghavan, 2016). According
to statistics released by the Instituto Nacional de Câncer José Alencar
Gomes da Silva (INCA), it is estimated that 600,000 new cases of can-
cer will be reported in Brasil between 2016 and 2017 (INCA, 2016).
Excluding cases of nonmelanoma skin cancer, the most frequent types
in men are prostate (28.6%), lung (8.1%), intestine (7.8%), stomach
(6.0%), and oral cavity (5.2%), whereas in women, mammary carcinoma
(28.1%), intestine (8.6%), cervix (7.9%), lung (5.3%), and stomach
(3.7%; INCA, 2016). Cancer is a set of heterogeneous genetic instabil-
ities linked by common alterations in multiple cell signaling pathways
(Luo, Solimini, Elledge, & Stephen, 2009). In this regard, numerous
markers have been identified as important mediators in cancer cells,
with apoptotic evasion reported as one of the major changes that
determine tumor growth (Hanahan & Weinberg, 2011). In addition,
other features may be included, such as self‐sufficiency in growth sig-
naling, cellular energy mismatch, sustained angiogenesis, evasion of
immune detection, and metastasis (Hanahan & Weinberg, 2000; Luo
et al., 2009). Cancer treatment methods include surgery, radiotherapy,
and anticancer drugs (chemotherapy), in addition to other specialized
techniques. Published reports indicated that approximately 90%–
95% of all cancers are due to lifestyle, such as alcohol consumption,
obesity, pollution, alcohol consumption, and food additives and the
remaining 5%–10% to defective genes (Rauf et al., 2018).
The optimal effect of treatment involves improving quality of life,
prolonging survival time, and lessening side effects. Thus, the concept
of “survival with cancer”has emerged (Qi et al., 2015). For years,
humans have used herbs as complementary therapy or dietary agents
to treat different types of cancer and to influence cellular signaling
(Martin, 2006). In this regard, natural compounds or natural dietary
agents, in particular spices and herbs, have attracted the attention of
scientists owing to their various properties in promoting health and
have been employed as alternative drugs in the treatment of cancer
(Kaefer & Milner, 2008). In this context, numerous reports have indi-
cated that compounds found in ginger can be effective in attenuating
the symptoms of chronic inflammatory disorders, as well as antitumor,
antioxidant, bactericidal, and antiviral agents (Manasa, Srinivas, &
Sowbhagya, 2013). Thus, they can provide a wide range of preventive
and therapeutic options against different types of cancer. In addition,
infusions prepared from ginger are popular folk remedies in several
countries for a wide range of diseases (Khaki & Fathiazad, 2012).
Alternative and complementary medicine, involving the use
medicinal plants as a source of therapeutic agents, has been used for
ages. In addition, phytochemicals extracted from medicinal plants have
been extensively studied in several countries and have been used to
treat various disorders including inflammation, hypertension, kidney
problems, immune deficiency, and cancer (Cragg & Newman, 2013).
The major phytochemical constituents that have shown promising
activities are secondary metabolites. They are widely distributed in
the plant kingdom and have been a great source in preventive and
therapeutic medicine, including anticancer drug molecules. In this con-
text, recent trends in cancer prevention revealed that ginger, its
extract, and single compounds, have promising biomedical impacts.
Ginger (Zingiber officinale), a spice widely utilized in food, is recognized
for its healing properties in traditional medicine. Ginger rhizome is
widely cultivated as a spice for its aromatic and pungent components,
including essential oil and oleoresins (Kaur, Deol, Kondepudi, &
Bishnoi, 2016). It was used in traditional medicine in the treatment
of various gastrointestinal diseases such as nausea, vomiting, abdomi-
nal discomforts, and diarrhea and for the treatment of arthritis, rheu-
matism, pain, muscle discomfort, cardiovascular, and metabolic
diseases. In addition to these documented properties, studies have
revealed that ginger exhibits anticancer properties in a wide variety
of experimental models (Tuntiwechapikul et al., 2010). Over a hundred
of compounds have been reported from ginger. These compounds
have been used in several food products such as soft beverages and
also in many types of pharmaceutical formulations. Among these,
[6]‐gingerol, the major component in ginger rhizomes, has shown sev-
eral interesting pharmacological and physiological activities. It exhib-
ited anti‐inflammatory, analgesic, and cardiotonic effects (Kubra &
Rao, 2012). The biologically active constituents of ginger include
gingerol, shogaol, paradol, and zingerone. Gingerol, or best known as
[6]‐gingerol (Figure 1) is identified as the main active constituent of
fresh ginger and is available in significant quantities in the fresh rhi-
zome. It is responsible for most of the pharmacological activities of
ginger described earlier (Chang & Kuo, 2015; Young & Chen, 2002).
On the other hand, shogaol can be derived from gingerols by elimina-
tion of the C‐5 hydroxyl and with consequent formation of a C‐4 and
C‐5 double bond (Benzie & Wachtel‐Galor, 2011; Jiang, 2005; Shukla
& Singh, 2007). Ju and coworkers have found that administration of
[6]‐gingerol inhibits tumor growth in several types of murine tumors,
such as B16F1 melanomas, Renca renal cell carcinomas, and CT26
colon carcinomas, in mice (Ju et al., 2012). A mixture of aqueous
FIGURE 1 Structure of [6]‐gingerol
2DE LIMA ET AL.

extracts from turmeric, ginger, and garlic showed free radical scaveng-
ing potential and anticancer properties against human breast cancer
cell lines (MCF‐7, ZR‐75, and MDA‐MB 231) (Vemuri et al., 2017).
The extract additionally induced apoptosis in all the breast cancer
cell lines by altering the expression of apoptotic markers (p53 and
caspase 9). Moreover, this extract showed a synergistically enhanced
proapoptotic effect when used in combination with tamoxifen as
compared with the extract alone (Vemuri et al., 2017). Components
of ginger when used in formulations of novel products may serve for
the purpose of pharmacological prevention of diseases.
On the other hand, deregulation of cell signaling pathways, caused
by increased or decreased expression of its protein constituents, can
lead to uncontrol of physiological events and trigger various types of
diseases, including cancer. Signal transduction occurs through signal-
ing pathways, which are usually composed of proteins involved in
the regulation of cellular events, such as cell proliferation, migration,
and differentiation (Souza, Araujo, Junior, & Morgado, 2014). Based
on the above discussion and owing to the wide range of preventive
and therapeutic options of ginger against various types of cancer, this
review focusses on the current knowledge of the chemo‐preventive
and therapeutic ability of ginger extracts (EGs) and [6]‐gingerol against
different types of cancer, along with mechanisms of action. In
addition, the current review evaluates the possible antioxidant and
anti‐inflammatory effects associated with tumor development.
2|METHODS
2.1 |Search strategy
Recent relevant references pertaining to EGs and [6]‐gingerol have
been obtained from different databases, such as Science Direct,
PubMed, Web of Knowledge, Medline, and Scopus for the period from
January to October 2017, using search descriptors, which include
“cancer,”“antioxidant,”and “inflammation”combined with “gingerol.”
Publications that have the terms described above in their titles or
keywords were included.
2.2 |Selection of studies for inclusion in the
systematic review
The following types of studies and investigations were included in this
review: (a) experimental in vitro/in vivo, (b) clinical, (c) studies that
include the use of EG and/or [6]‐gingerol, (d) studies that indicate
the concentrations or doses employed and the form of administration,
and (e) studies that point out to the mechanisms of action associated
with the extract treatment and isolated ginger derivatives.
2.3 |Data extraction
Data of each publication that meet the inclusion criteria were
extracted according to surname of first author, year of publication,
type and method of study, isolated compound and/or EG, concentra-
tions tested, molecular mechanism involved, and main results
obtained.
3|RESULTS AND DISCUSSION
The search strategy identified 5,082 publications from PubMed
(1,606), Science Direct (2,099), Web of Knowledge (595), Medline
(204), and Scopus (578) databases. Three thousand eight hundred
and seventy nine (3,879) items were excluded because they did not
conform to the descriptors combination, whereas 667 were excluded
due to duplication.
In the systematic review (qualitative synthesis), 131 publications
were read in full, 96 of them were not adequate because they did
not present mechanisms of action associated with the treatment of
extract and ginger and [6]‐gingerol, whereas 35 articles were used in
the present review. Studies evaluated were published between 2000
and 2017, and those that met the criteria established cover the time
period from 2005 to 2017; these are listed in an ascending order
according to year of publication.
Common extraction procedures for ginger involve hydrodistillation,
steam distillation, and solvent extraction. Solvent extraction with ace-
tone resulted in a high ginger oleoresin content, which contains the
essential oils as well as the pungent principles and other nonvolatile
compounds present in ginger (McLaughlin, 2005). Additionally, ginger
rhizhome extraction in acetone or ethanol resulted in isolation of
gingerols (about 33%); however, extraction of ginger with ethyl ether,
acetone, and hexane solvents has been established and is the preferred
method. On the other hand, ethyl acetate extracted ginger was shown
to have potent antioxidant activity. Similarly, microwave‐assisted
extraction of gingerol is also an efficient process, which results in
increased total polyphenol content. Microwave‐dried extract showed
the highest quantity (1.5 fold) in TPP, [6]‐gingerol content, and antioxi-
dant activity when compared with the cross‐flow dried extract (Kubra
& Rao, 2012a). Moreover, a study focusing on extraction procedures
for gingerol demonstrated that extraction temperature (50–80 °C) and
extraction time (2–4 hr) are also important aspects (Ghasemzadeh,
Jaafar, & Rahmat, 2015).
3.1 |Role of ROS in the body and oxidative stress
Reactive oxygen species (ROS) play an intriguing role in cells of normal
and diseased phenotype through a number of mechanisms. Under nor-
mal physiological conditions, limited ROS generation assists in main-
taining cellular homeostasis with the help of insulin, cytokines, and
many growth factors (Sundaresan, Yu, Ferrans, Irani, & Finkel, 1995),
leading to regulation of classical signaling cascades such as extracellu-
lar ERK, JNK, and mitogen‐activated protein kinase (MAPK), including
PI3‐K/Akt, PLC‐γ1, and JAK/STAT pathways (Droge, 2002). These
pathways, in turn, exert their phenotypic effects, largely, by modulat-
ing the activities of central transcription factors, including NF‐κB,
AP1, Nrf2, FoxOs, HIF‐1α, and p53 (Hamanaka & Chandel, 2010;
Trachootham, Lu, Ogasawara, Valle, & Huang, 2008). Furthermore,
activities of enzymes such as catalase, glutathione peroxidase, and
peroxiredoxins regulated by kinases and phosphatases are susceptible
to oxidative modification, thus creating a regulatory network (Flohe,
2010; Yu, 1994). At high levels, ROS can promote damage to several
molecules, including DNA, that may trigger carcinogenic developments
(Liou & Storz, 2010; Sundaresan et al., 1995; Waris & Ahsan, 2006).
DE LIMA ET AL.3

In cancer patients, oxidative stress alters the expression of genes
that inhibit cell cycle progression (called tumor suppressor genes) and
thus increases proliferation of cancer cells (Afanas, 2014). Additionally,
ROS promote expression of proteins involved in the control of inflam-
mation, cell transformation, tumor cell survival, proliferation, invasion,
angiogenesis, and metastasis. They also play an important role in the
transformation of normal cells into carcinogens. In this respect, higher
levels of ROS were identified in tumor cells than in normal cells.
Collectively, reactive oxygen species play a dual role, they can kill
cancer cells or promote tumor survival (Gupta et al., 2012; Krystona,
Georgieva, Pissis, & Georgakilas, 2011). High amounts of ROS are
detected in almost all types of cancer, where they promote many
aspects related to the development of the tumor (Liou & Storz,
2010). Although ROS are protumorigenic, their high concentration
may be toxic to even cancer cells. However, cancer cells also maintain
elevated levels of antioxidant proteins expression that detoxify excess
ROS. This indicates a necessary balance of intracellular ROS genera-
tion and quenching processes (Nogueira & Hay, 2013).
3.2 |Antioxidant effect of [6]‐gingerol and EG
Antioxidants are substances, present in low concentrations when
compared with the oxidizable substrate, which delay or inhibit its oxi-
dation. These antioxidants protect the body from damage caused by
the action of free radicals (Dias, Moura, & D'Angeliz, 2011; Machado,
Nagem, Peters, Fonseca, & Oliveira, 2010). Antioxidants exert their
action through different mechanisms of action, which include
preventing the formation of free radicals (prevention systems),
preventing the action of these reactive species (sweep systems), or
even repair and reconstitute structures of biological damage (repair
systems; Clarkson & Thompson, 2000; Koury & Donangelo, 2003).
Free radicals generated from antioxidants are not reactive to the point
of propagating the chain reaction. They react with other radicals and
form stable products or can be recycled by other antioxidants
(Barreiros, David, & David, 2006; Omoni & Aluko, 2005).
According to their mode of action, antioxidants can still be classi-
fied into primary and secondary. Primary antioxidants act by
interrupting the chain of reaction by donating electrons or hydrogen
atoms to free radicals, thus converting them into thermodynamically
stable products and/or reacting with free radicals to form the antioxi-
dant lipid complex that can react with other free radicals. On the other
hand, secondary antioxidants act by delaying the initiation stages of
autoxidation by different mechanisms, which include metal complexa-
tion, oxygen sequestration, decomposition of hydroperoxides to form
nonradical species, absorption of ultraviolet radiation, and deactiva-
tion of singlet oxygen (Sousa et al., 2007). In the enzymatic antioxidant
defense system, the enzymes superoxide dismutase, glutathione
peroxidase, and catalases are present. These substances can remove
oxygen or highly reactive compounds, react with oxidizing com-
pounds, and protect cells and tissues from oxidative stress (Giustarini,
Dalle‐Donne, Tsikas, & Rossi, 2009). Nonenzymatic components of
the antioxidant defense involves (a) minerals such as copper, manga-
nese, zinc, selenium, and iron; (b) vitamins such as ascorbic acid,
vitamin E, and vitamin A; (c) carotenoids such as beta‐carotene,
lycopene, and lutein; (d) bioflavonoids such as genistein and quercetin;
and (e) tannins such as catechins (Papas, 1999).
Natural products contain a large number of phytochemicals and
phenolic compounds that are associated with low occurrence of can-
cer in humans. Numerous studies indicated that consumption of foods
rich in antioxidants provide protection against oxidative processes
(Yildrin, Mavi, & Kara, 2001). The use of crude and phytochemical
extracts isolated from medicinal plants is gaining popularity and is
becoming more acceptable and preferable, possibly due to the cost
of production, availability, and accessibility, as well as lower toxicity
in most cases (Yehya et al., 2017). A large number of natural antioxi-
dants have been isolated from different types of plant materials, such
as oil seeds, cereals, vegetables, fruits, leaves, roots, spices, aromatic
herbs, among others (Jayakumar, Thomas, & Geraldine, 2009). In this
context, [6]‐gingerol, a naturally occurring phenol obtained from edi-
ble ginger (Z. officinale), exhibits antioxidant, anti‐inflammatory, free
radical scavenging, antitumor, and antiendocrine activity. In addition,
it acts as an immunomodulator, antiosteoarthritis, and antimicrobial
agent (Oyagbemi, Saba, & Azeez, 2010; Prasad & Tyagi, 2015a;
Srinivasan, 2014).
Based on the antioxidant mechanisms, Table 1 shows the protec-
tive effects of EG and/or [6]‐gingerol in experimental (in vivo and
in vitro) and clinical studies as antioxidants. Lee, Park, Kim, and Jang
(2011) evaluated the effect of [6]‐gingerol on human neuroblast line-
age (SHSY5Y) exposed to β‐amyloid peptide (Aβ25–35), which is
involved in the formation of senile plaques, and is a typical neuro-
pathological marker for Alzheimer's disease. These researchers
showed that pretreatment with [6]‐gingerol (10 μM) significantly
reduced Aβ25–35‐induced cytotoxicity; reduced the levels of
malondialdehyde (MDA), ROS, and peroxynitrite (ONOO‐); and
increased the level of intracellular glutathione (GSH), thus suppress-
ing oxidative and/or nitrosative damage induced by excess Aβ25–
35. It was additionally found that pretreatment with [6]‐gingerol
effectively suppresses the increase of Bax/Bcl2 ratio and reduces
caspase‐3 activation, increases phosphorylation, nuclear transloca-
tion, and subsequent transcriptional activation of nuclear erythroid
2 related to factor 2 (Nrf2; Lee et al., 2011). These results suggest
that [6]‐gingerol displays preventive and therapeutic potential that
can be employed for the management of Alzheimer's disease through
its antioxidant activity.
Under basal conditions, Nrf2 is mainly regulated by the Kelch‐like
ECH‐associated protein 1 (Keap1), an adaptor subunit of Culina (Cul3)‐
Rbx 1 E3 ubiquitin ligase that mediates proteasomal degradation of
Nrf2. Oxidative stress leads to conformational changes in the Nrf2‐
Keap1‐Cul3 complex that activates Nrf2. Activated Nrf2 translocates
to the nucleus and binds to the antioxidant response element (ARE)
in the promoter region of Nrf2 target genes. Binding of Nrf2 to ARE
results in synchronized activation of a battery of detoxification
enzymes and antioxidants. Phytochemicals present in foods react spe-
cifically with the cysteine residues of Keap1, leading to a conforma-
tional change, which results in a decreased Nrf2 labeling for
proteolysis (Duan et al., 2016; Niture & Jaiswal, 2012). In this context,
the expression of Nrf2 and its downstream genes is dramatically
enhanced by treatment with ginger phenols (gingerol/shogaol; Bak,
Ok, Jun, & Jeong, 2012).
4DE LIMA ET AL.

Schadich and colleagues evaluated the effects of the phenols
present in EG on the activation of the Nrf2‐ARE pathway and on
the expression of phase II detoxification enzyme glutathione‐S‐trans-
ferase P1 (GSTP1) in immortalized keratinocyte cells (HaCaT) and fore-
skin fibroblasts. These researchers found a significant increase in the
level of Nrf2 activity and that the increased level of Nrf2 in treated
HaCaT cells was not associated with an increased GSTP1 enzyme level
(Schadich et al., 2016). In HaCaT cells, regulation of Nrf2 independent
of GSTP1 expression may have evolved selectively with high
proliferation capacity during immortalization (an ability to proliferate
an unlimited number of times). As immortalization is a first step in car-
cinogenesis, a variety of human cancer cells, including breast, colon,
kidney, lung, and ovary cancer cells, share genomic instability, loss of
senescence genes, p53 mutation, and high expression of GSTP1
(Howells et al., 2004; Tidefelt et al., 1992; Yamamoto et al., 2013).
Additionally, the role of GSTP1 in HaCaT cells may be distinct from
normal cells (Schadich et al., 2016). Although ginger has many bioac-
tive compounds with pharmacological activities, only few of these
TABLE 1 Antioxidant effect of [6]‐gingerol and ginger extract (EG)
Form of use
Method of study Mechanism of action EG
and/or [6]‐gingerol ReferenceDose or concentration
EG In vivo—Male Wistar rats (N= 50) ginger effect in
the initiation and postinitiation stages of colon
carcinogenesis induced by 1,2‐
dimethylhydrazine
(DMH)—15 weeks—intraperitoneal route
Administration of EG (50 mg/kg/day)—28 days—
oral—gastric tube
Decreases lipid peroxidation
Increases GSx, GST, GR,
SOD, and CAT
(Manju & Nalini, 2005)
[6]‐G In vitro—Exposure of SHSY5Y to Aβ25‐35,
(2.5, 7.5, 20 μM) and treatment with
[6]‐G (10 μM)
Decreases cytotoxicity
induced by Aβ25–35
Decreases MDA, ROS,
ONOO
−
, Bax/Bcl2 ratio,
caspase‐3
Increases GSH; Nrf2/ARE
(Lee, Park, Kim,
& Jang, 2011)
EG In vivo—Male Wistar (N= 8) albino rats with
hepatic fibrosis induced by carbon
tetrachloride (CCl4).
Induction: CCl4 (0.5 ml/kg) intraperitoneally,
six consecutive weeks, two times a week
Group EG: 200 mg/kg—oral
Increases GSH, SOD, SDH,
LDH, G6Pase, AP, and 5′NT
Decreases MDA, AST, ALT,
ALP, GGT, and total bilirubin
(Motawi, Hamed, Shabana,
Hashem, & Naser, 2011)
EG In vitro—Treatment of the cardiomyocyte
(H9c2) line with EG (6–200 μg/ml) +
DOX (5 μg/ml)
Decreases MDA and ROS
Decreases DOX‐induced
apoptosis
(Hosseini, Shafiee‐Nick,
& Mousavi, 2014)
EG In vitro—Treatment of HaCaT and BJ lines
using EG (40 μg/ml)
Increases Nrf2
Increases GSTP1 cell line BJ
(Schadich et al., 2016)
EG In vivo—Male Wistar rats (N= 10)
Exposure to aflatoxin B1 (AFB 1) 200 μg/kg—28
alternate days—intraperitoneal
Treatment of EG (100 and 250 mg/kg/day)—28
days—oral—gastric tube
Increases Nrf2 and HO‐1
Increase antioxidant enzymes
(SOD, CAT, and GST)
Decreases MDA
(Vipin, Raksha Rao, Kurrey,
Anu Appaiah, &
Venkateswaran, 2017)
EG In vitro—Effect of EG on aflatoxin B1 (AFB1)
in HepG2 human hepatoma line.
HepG2 pretreatment with EG (0–200 μg/ml)
Exposure HepG2 to AFB1 (0–50 μM)
Decreases ROS (Vipin et al., 2017)
[6]‐G In vivo—Sprague–Dawley (N= 8) rats with
ischemic intestinal reperfusion injury (I/R)
Pretreatment with [6]‐G 25 mg/kg—three
consecutive days prior to reperfusion—oral
Inhibition of the MAPK p38 pathway
Increases SOD, GSH, and GSHP
Decreases MDA
(Li et al., 2017)
[6]‐G In vitro—[6]‐gingerol effects on Caco‐2 and
IEC‐6 lines under conditions of hypoxia/
reoxygenation (H/R)
Pretreatment Caco‐2 and IEC‐6 with [6]‐gingerol
(5, 10, 20, 40, 80, and 160 μM)
Decreases ROS
Inhibition of phosphorylation of
p38 MAPK, p65 NF‐κB, and MLCK.
(Li et al., 2017)
EG/[6]‐G
standardized
Clinical—43 patients newly diagnosed with
cancer (19 ginger group and 24 placebo)
Administration of two capsules 2 g/day—3
days—oral before the first cycle and during
chemotherapy until the fourth cycle.
Increases antioxidant enzymes
(SOD, CAT, and GSH/GSSG)
Decreases MDA
Decreases NO2/NO3
(Danwilai, Konmun,
Sripanidkulchai,
& Subongkot, 2017)
Note.Aβ25–35: β‐amyloid; GSH: Glutathione; GSx: glutathione peroxidase; GST: Glutathione S‐transferase; GR: glutathione reductase; SOD: superoxide
dismutase; MDA: malondialdehyde; ONOO‐: peroxynitrite; Nrf2: Factor 2 erythroid‐related Factor 2, LDH: lactate dehydrogenases; G6Pase: glucose‐6‐
phosphatase; AP: acid phosphatase, 5′NT: 5′nucleotidase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GPx‐1: phosphatase glutathi-
one peroxidase‐1; MLCK: myosinase kinase; GSTP1: glutathione S‐transferase P1; CAT: catalase; ROS: reactive oxygen species; ARE: antioxidant response
element; SDH: sorbitol dehydrogenase; ALP: alkaline phosphatase; GGT: gamma‐glutamyl transferase; DOX: doxorubicin; GSSG: glutathione disulfide.
DE LIMA ET AL.5

have been tested for their activity in chemoresistant cells. The protein
expression of multidrug resistance associated protein 1 (MRP1)
and glutathione‐S‐transferase (GSTπ) is higher in chemoresistant pros-
tate cancer cell PC3R than in PC3. Liu, Kao, Tseng, Lo, and Chen
(2017) isolated [6]‐gingerol, [10]‐gingerol, [4]‐shogaol, [6]‐shogaol,
[10]‐shogaol, and [6]‐dehydrogingerdione from ginger and tested their
anticancer properties in docetaxel‐resistant (PC3R) and sensitive (PC3)
human prostate cancer cells. These compounds significantly inhibited
the proliferation of cells through downregulation of MRP1 and GSTπ
(Liu et al., 2017).
Although cytoprotection provided by activation of Nrf2 is impor-
tant for chemoprevention of cancer in normal and premalignant
tissues in completely malignant cells, Nrf2 activity provides growth
advantage by increasing cancer chemoresistance and by increasing
tumor cell growth. The constitutively abundant Nrf2 protein causes
increased expression of genes involved in drug metabolism, thus
increasing resistance to chemotherapeutic drugs and radiotherapy. In
addition, high levels of Nrf2 protein affect cell proliferation by
targeting glucose and glutamine, increasing purine synthesis, and
influencing the pentose phosphate pathway to promote cell prolifera-
tion (Mitsuishi et al., 2012).
On the other hand, the metabolic balance of oxygen in the intra-
cellular environment is maintained by antioxidant enzymes, also
known as phase II detoxification enzymes, such as heme oxygenase
1 (HO‐1). Production of these enzymes occurs through activation of
Nrf2/ARE antioxidant signaling pathway, by means of several sub-
stances investigated with antioxidant potential (Lee et al., 2015; Xia,
Liu, Xie, Wu, & Li, 2015). Vipin, Raksha Rao, Kurrey, Anu Appaiah,
and Venkateswaran (2017) have demonstrated that pretreatment with
EG protects HepG2 cells against aflatoxin B1‐induced cytotoxicity
through inhibition of ROS generation, DNA damage, and cell death.
Similarly, mouse model experiments revealed the protective effects
of EG against AFB1‐induced hepatotoxicity by improving antioxidant
enzyme levels and by upregulation of the Nrf2/HO‐1 pathway. The
hepatoprotective properties of EG may be due to synergistic effects
of different phenolic compounds present therein. According to Wang
et al. (2016), antioxidant substances act by inhibiting the excess
production of ROS.
Induction of Nrf2 signaling is associated with prevention of hepa-
totoxicity both in vivo and in vitro. Nrf2 is mainly expressed in meta-
bolically active organs such as the liver. Therefore, Nrf2 is consideredas
a key therapeutic target for prevention and treatment of liver diseases
(Eggler, Gay, & Mesecar, 2008; Lee & Surh, 2005; Zhu et al., 2016). In
addition, Nrf2 is important in chronic diseases involving oxidative stress
such as inflammatory, neurodegenerative, and cancer diseases (Kaspar,
Niture, & Jaiswal, 2009; Kensler, Wakabayashi, & Biswal, 2007).
Furthermore, oxidative stress plays a key role in intestinal H/R
injury (Wen et al., 2013). ROS are generated in damaged tissues and
cells and trigger activation of a variety of signaling pathways, promot-
ing inflammatory reaction, and damaging the intestinal mucosal barrier
function in the H/R process (Bhattacharyya, Chattopadhyay, Mitra, &
Crowe, 2014). The signaling pathway of mitogen‐activated p38 pro-
tein kinase (p38 MAPK) mediates inflammatory, apoptotic response,
and differentiation under stress conditions, including H/R lesions
(Coulthard, White, Jones, Mcdermott, & Burchill, 2009; Yong, Koh, &
Moon, 2009; Zhang, Shen, & Lin, 2007). Under stress conditions, intra-
cellular p38 can be transferred to the nucleus, and expression of genes
involved in the regulation of transcription factors is regulated by
phosphorylation (Wehner et al., 2009; Yang et al., 2015). In a similar
fashion, myosin light chain kinase (MLCK) is a protein kinase closely
related to the barrier function. The MLCK‐mediated myosin light chain
phosphorylation is associated with cytoskeletal contraction and leak-
age junction (tight junction [TJ]) dysfunction, which may impair the
intestinal mucosal barrier function (Al‐Sadi et al., 2013; Cunningham
& Turner, 2012; Su et al., 2013). Similarly, the p38 MAPK pathway is
involved in the MLCK‐mediated modulation in the barrier function
(Al‐Sadi et al., 2013; Araki et al., 2005; Zou et al., 2015).
In Caco2 (human colon adenocarcinoma) and IEC6 (murine normal
intestinal epithelium) cells under H/R conditions, expression of NF‐κB,
MAPK, and MLCK proteins was significantly increased. However, pre-
treatment with [6]‐gingerol exerted inhibitory effects depending on
the concentration. Additionally, [6]‐gingerol suppressed phosphoryla-
tion of p65 which is a critical subunit in the modulation of NF‐κB
nuclear translocation, and decreased MLCK protein expression and
phosphorylation of p38 MAPK in a concentration‐dependent manner,
highlighting the important role in suppression of [6]‐gingerol‐induced
p38 MAPK in H/R model. Moreover, research findings indicated that
drugs that improve oxidative stress, relieve inflammation, and pain,
inhibit bacterial growth, and modulate barrier dysfunction are benefi-
cial for the improvement of intestinal lesion (Li et al., 2017).
Li and coworkers investigated the effect of [6]‐gingerol on rat
intestinal ischemic–reperfusion (I/R) injury. These workers found that
treatment of rats with this compound alleviated intestinal injury in I/
R injured rats. This was achieved by significantly increasing levels of
superoxide dismutase (SOD), GSH, and glutathione peroxidase and
by substantially decreasing the level of MDA. These results suggest
that [6]‐gingerol provides protective effects against I/R‐induced intes-
tinal mucosa injury by impeding generation of ROS and p38 MAPK
activation, providing insights into the mechanisms of this therapeutic
candidate for the treatment of intestinal injury (Li et al., 2017). On
the other hand, carbon tetrachloride (CCl
4
) is a known hepatotoxin
widely used in the induction of toxic liver injury in laboratory animals
(Lee et al., 2007; Pereira‐Filho et al., 2008). The initial phase
involves metabolism of CCl
4
by cytochrome P‐450 to trichloromethyl
radical (CCl
3
•
). Some of these trichloromethyl radicals generate
trichloromethyl peroxyl radical (OOCCl
3
•
), which leads to lipid peroxi-
dation. In this regard, Motawi, Hamed, Shabana, Hashem, and Naser
(2011) reported that treatment of rats with hepatic fibrosis induced
by carbon tetrachloride, with EG showed a significant increase in
GSH, SOD, SDH, LDH, G6Pase, AP, and 5'NT. However, MDA, AST,
ALT ALP, GGT, and total bilirubin were significantly decreased.
Similarly, ginger supplementation at the initiation and postinitiation
stages of colon carcinogenesis induced by 1,2‐dimethylhydrazine
significantly increased nonenzymatic and enzymatic antioxidant
concentrations compared with the nonginger supplemented group
(Manju & Nalini, 2005).
In a recently published clinical investigation, the antioxidant activ-
ity of EG oral supplement in newly diagnosed cancer patients receiv-
ing adjuvant chemotherapy compared with placebo was examined.
Results revealed that antioxidant activity parameters including SOD,
6DE LIMA ET AL.

CAT, GPx, and GSH/GSSG were significantly increased at Day 64 with
patients who received two EG capsules standardized with 5 mg of [6]‐
gingerol (1.4% w/w EG) 3 days prior to the first cycle of chemother-
apy, and continued on this supplement to the fourth cycle, compared
with the placebo group. On the other hand, MDA and NO
2
−
/NO
3
−
levels were significantly lower than the treated group (Danwilai,
Konmun, Sripanidkulchai, & Subongkot, 2017).
Similarly, doxorubicin (DOX) is an important component in the
multimodal therapy of various combined antineoplastic protocols in
chemotherapy. However, despite its high efficacy, DOX's main side
effect of cardiotoxicity drastically prevents its clinical use for extended
periods. There is much evidence that the protective effects of natural
compounds against cardiotoxicity is related to oxidative damage.
These compounds lessen some side effects of chemotherapeutic
agents in normal cells and thus reduce their genotoxicity (Bryant
et al., 2007; Wu et al., 2002). Research findings demonstrated that
EG exerts a protective role against DOX‐induced toxicity in
cardiomyocytes (H9c2), as shown by reduction in the level of lipid per-
oxidation, ROS, and suppression of apoptosis induced by doxorubicin
in H9c2 (Hosseini, Shafiee‐Nick, & Mousavi, 2014).
3.3 |Inflammation and cancer
Inflammation is a protective immune response of a vascular organism
that assists in the removal of internal and/or external harmful stimuli
and operates to maintain tissue homeostasis (Serhan, 2014). The
inflammatory reaction basically comprises two defense mechanisms:
a nonspecific response (innate response) and a specific immune
response (acquired response; Coutinho, Muzitano, & Costa, 2009).
At the beginning of an inflammatory response due to tissue aggres-
sion, invasive inflammatory cells produce several proinflammatory
mediators that increase the degree of local and systemic inflammation
(Melo, Yugar‐Todelo, Coca, & Júnior, 2007), depending on the type of
infection: bacterial, viral, or parasitic (Medzhitov, 2010).
An infection in any tissue rapidly attracts white blood cells to the
affected region as part of the inflammatory response, which helps to
fight infection and in wound healing (Alberts et al., 2010). However,
the initial inflammatory response is not always sufficient, and the pro-
cess may progress to a state of chronic inflammation (Coutinho et al.,
2009). If the agent that causes infection is not completely cleared by
the acute inflammatory response, or it persists for some reason, a
chronic inflammation may result. This condition can be caused by
chronic infections, persistent allergens, and foreign particles or endog-
enous crystals (Medzhitov, 2010). Moreover, when the inflammatory
response is uncontrolled, it becomes harmful to the body. Although
symptoms and signs of chronic inflammation are not as severe as
those of acute inflammation, chronic inflammation is typically more
risky as it can cause additional damage like fibrosis, and can cause
chronic and systemic diseases such as rheumatoid arthritis, asthma,
diabetes, inflammatory bowel diseases, cardiovascular diseases, neuro-
logical disorders (Alzheimer's), age‐related muscular degeneration, and
cancer (Mantovani, Allavena, Sica, & Balkwill, 2008; Serhan & Petasis,
2011).
Chronic inflammation is linked to several stages of tumorigenesis
such as cell proliferation, transformation, evasion of apoptosis,
survival, invasion, angiogenesis, and metastasis (Aggarwal, Shishodia,
Sandur, Pandey, & Sethi, 2006; Demaria et al., 2010). Inflammation is
additionally known to contribute to carcinogenesis by generation of
ROS and reactive nitrogen species that can damage DNA at the tumor
site (Ohnishi et al., 2013). Furthermore, the inflammatory medium pro-
motes a cellular microenvironment that favors expansion of genomic
aberrations and initiation of carcinogenesis (Mantovani, 2009). Studies
suggest that approximately 25% of cancers are etiologic in inflamma-
tion and/or chronic infection (Kundu & Surh, 2012). In the tumor
microenvironment, inflammatory cells are induced to accelerate cancer
progression, metastasis, and immune responses against radiation ther-
apy, chemotherapy, and immunotherapy (Gajewski, Schreiber, & Fu,
2013). Therefore, the direction of the inflammatory microenvironment
is a reasonable direction for cancer treatment (Q. Zhang, Zhu, & Li, 2017).
3.4 |Mediators of the inflammatory process in the
tumor microenvironment
Acute inflammation triggers cellular repair response for damaged tis-
sues leading to tissue homeostasis. Under normal conditions, immune
cells including macrophages, granulocytes, mast cells, dendritic cells,
innate lymphocytes, and natural killer cells serve as a front line
defense against pathogens (Coussens, Zitvogel, & Palucka, 2013;
Serhan, 2014). However, in tumor microenvironment, chronic inflam-
mation of “damaged”(tumor) tissue may result. Thus, while acute
inflammation normally supports and balances two opposing needs
for the repair of damaged tissues (apoptosis and wound healing),
chronic inflammation represents a loss of this balance (Khatami, 2009).
Several mechanisms exist by which inflammation contributes to
carcinogenesis, including altered biochemical processes such as a high
expression, overproduction, or abnormal activation of several inflam-
matory mediators, with cytokines, chemokines, cyclooxygenase‐2
(NOS), nitric oxide (NO), and advanced glycosylation products (Kundu
& Surh, 2012). Chronic inflammatory cells can induce genomic instabil-
ity, alterations in epigenetic events and inappropriate gene expression
(Colotta, Allavena, Sica, Garlanda, & Mantovani, 2009; Kundu & Surh,
2008). During tumor progression, cytokines and chemokines produced
by immune and inflammatory cells facilitate the survival and prolifera-
tion of cancer cells and promote angiogenic tumor growth (Mantovani,
2005). Cytokines and chemokines also induce additional recruitment
and differentiation of immune cells in the tumor microenvironment
(Lin & Karin, 2007). The genetic regulation that leads to secretion of
proinflammatory cytokines from a variety of cells is generally depen-
dent on the transcriptional activation of nuclear factor‐kappa B
(NF‐κB; Freire & Van Dyke, 2014). This factor could be considered
as a “nucleus”in the tumorigenesis that links cellular senescence,
inflammation, and cancer (Aggarwal & Gehlot, 2009). Inflammation is
characterized by an overall increase in plasma levels and cellular
capacity to produce proinflammatory cytokines such as interleukin
(IL) 6, IL‐1, tumor necrosis factor (TNF)‐α, and a subsequent increase
in the main inflammatory markers such as C‐reactive protein and
serum amyloid A (Franceschi, 2007; Franceschi et al., 2000). TNF,
known for its tumor cytotoxicity, is a cytokine involved in systemic
inflammation and stimulation of the acute phase reaction (Sedger &
Mcdermott, 2014). On the other hand, products derived from COX‐
DE LIMA ET AL.7

2, mainly prostaglandin (PG) E2 (thought to be the major tumorigenic
COX‐2 product), are known to act not only on classical pathways of
cancer signaling to promote carcinogenesis in tumor cells but also in
the tumor microenvironment that contains multiple resident and infil-
trating cells (including immune cells), as well as on the growth factors
and cytokines released by them (Bonaccio et al., 2014; Hanahan &
Weinberg, 2011). Consequently, the relationship between inflamma-
tion and cancer that promotes tumors is important to consider.
Overall, mechanisms involving abnormal activation of inflammatory
mediators that contribute to the development of tumor microenviron-
ment are depicted in Figure 2. In this respect, macrophage migration
inhibitory factor, COX‐2, NF‐κB, TNF‐α, inducible nitric oxide
synthase (iNOS), and Akt and chemokines are important targets that
may be appropriate for a multifaceted therapeutic approach in
suppressing inflammation (Block et al., 2015).
Based on reports on anti‐inflammatory mechanisms, Table 2
shows the suppressive effects of EG and/or [6]‐gingerol on inflamma-
tory responses associated with chronic and systemic diseases, with
emphasis on carcinogenesis, and on experimental and clinical studies
in the face of factors released during chronic inflammation. In addition,
EG significantly reduced the elevated expression of NF‐κB and TNF‐α
in rats with hepatic cancer, suggesting that ginger can act as an anti-
cancer and anti‐inflammatory agent; it inactivates the NF‐κBby
suppression of proinflammatory TNF‐α. Although this factor is
expressed in an inactive state in most cells, cancer cells express an
activated form of NF‐κB induced by various inflammatory and carcino-
genic stimuli (Lin & Karin, 2003). Furthermore, TNF‐α, interleukins,
COX‐2, and other chemokines can also be regulated by the NF‐κB
transcription factor (Balkwill, 2002). In this context, numerous studies
have associated the NF‐κB signaling pathway and its regulation with
the inflammatory response (Escarcega, Fuentes‐Alexandro, Garcia‐
Carrasco, Gatica, & Zamora, 2007; Lin & Karin, 2003). NF‐κB acts as
transcriptional regulator for Bcl‐2 family of apoptosis related poteins.
In a carcinogenic process, it mediates the altered expression of
proapoptotic and antiapoptotic Bcl‐2 family proteins. These observa-
tions suggest that inhibition of the NF‐κB signaling pathway
might be a therapeutic strategy in conjunction with the use of chemo-
preventive agents such as ginger (Kim, Chun, Kundu, & Surh, 2004;
Surh, 2003).
Lipopolysaccharide (LPS), the main constituent of the outer cell
wall of Gram‐negative bacteria, has been widely used to examine
inflammation mechanisms that produce typical hepatic necrosis
followed by fulminant hepatic failure (Vincent, Sun, & Dubois, 2002).
It was found that, under stimulation of LPS, Kupffer cells release pro-
inflammatory cytokines (Bølling, Samuelsen, Morisbak, Ansteinsson, &
Becker, 2013). Activation of LPS‐induced NF‐κB mediates MAPKs,
and subsequently regulates COX‐2 expression, and inducible expres-
sions of nitric oxide synthase (iNOS; Mestre et al., 2001). In addition,
expressions of COX‐2 and iNOS contribute to inflammatory diseases
(Jacobs & Ignarro, 2001). Therefore, these cytokines represent an ideal
target for neutralization of LPS (Wyckoff, Raetz, & Jackman, 1998).
Furthermore, prolonged use of anti‐inflammatory drugs is associated
with side effects such as fever, flushing, and sore muscles. In this case,
the use of a natural product to treat inflammatory diseases may be
more effective with fewer side effects (Wong et al., 2003).
Elevated levels of prostaglandin E (PGE) in the tissue, produced by
COX, is an early event in colorectal cancer (CRC). Jiang et al. (2013)
observed no significant difference in COX‐1 protein expression
between the ginger and placebo groups of participants at normal risk.
However, results indicated that, for patients at increased risk of colo-
rectal cancer, COX‐1 protein expression in colon biopsies was signifi-
cantly inhibited by consumption of ginger root extract after 28 days of
intervention compared with the placebo group. Healthy and tumor
cells share the same origin; thus, it is difficult to develop selective
drugs that are based on biochemical differences between cancer and
healthy cells. Consequently, researchers and clinicians need a new
perspective and, for this reason, signaling pathways are being inten-
sively investigated to gain ground in the fight against cancer. Inhibition
FIGURE 2 Mechanisms involving abnormal
activation of inflammatory mediators that
contribute to the development of tumor
microenvironment [Colour figure can be
viewed at wileyonlinelibrary.com]
8DE LIMA ET AL.

TABLE 2 Anti‐inflammatory effect of ginger extract (EG) and/or [6]‐gingerol
Form of use
Method of study Mechanism of action
EG and/or [6]‐G ReferenceDose or concentration
EG In vivo—Effect of ginger on ethionine‐induced hepatocarcinogenesis,
male Wistar rats (N=6)
Induction of hepatic cancer with ethionine—15 weeks—intraperitoneal route
Food/olive oil controls; EG (100 mg/kg); choline deficient diet (CDE) + 0.1%
ethionine; ginger + CDE. 8 weeks—oral
Decreases NF‐κB
Decreases TNF‐α
(Habib et al., 2008)
EG In vivo—To characterize the possible anti‐inflammatory effects of lipopolysaccharide
(LPS)‐induced EG in female rats (N‐5)
Pretreatment with EG 100, 1,000 mg/kg—3 days in a row—oral
Third day—LPS administration —35 mg/kg—intraperitoneal
Decreases activation IFNy,
IL‐6,
NF‐κB, and I?B‐a
Decreases expression MAPKs
(ERK1/2, SAPK/JNK, and p38)
Decreases iNOS and COX‐2
expression
(Choi, Kim, Hong, Kim,
& Yang, 2013)
EG Clinical—To verify the efficacy of EG in the regulation of PGE2 in patients with normal
and increased risk of CRC
Administration of eight capsules 250 mg each for 28 days, followed by biopsy tissue colon
Normal group (N= 30); increased risk—CRC (N= 20)
Decreases COX‐1 (group at
increased risk CRC)
(Jiang et al., 2013)
[6]‐G In vitro—Effect of [6]‐G on human hepatocyte (HuH7) lineage
Cell viability [6]‐G (50, 100, and 200 μM)
HuH7 exposed to cytokine IL‐1β(8 ng/ml) and treated with [6]‐G (100 μM)
Decreases IL‐6, IL‐8, SAA1,
COX, NF‐κB, and ROS
Inhibition via ROS/NF‐κB/
COX‐2
(Li et al., 2013)
[6]‐G In vitro—Effects of [6]‐G on human MG63 osteoblast‐like lineage
Exposure of MG63 line (1 × 105) to pretreatment TNF‐α(10 ng/ml) and treatment
[6]‐gingerol (0, 1, 5, 10, and 50 μM)
Increases ALP enzyme (Fan, Yang, & Bi, 2015)
EG padronizado com 5% [6]‐G In vivo—Albino Wistar rats of both sexes (N= 15)
Induction diabetes: single dose of STZ 45 mg/kg—intraperitoneal route
Treatment: 75 mg/kg/day/24 weeks—oral
Treated group EG/5% [6]‐G
Decreases TNF‐α
Decreases NF‐κB p65
Decreases VEGF
(Dongare et al., 2016)
[6]‐G In vitro‐effect of [6]‐gingerol on LTA 4 H in human tumor line (HCT116) and
normal cells (TIG1 and HF19) exposed to [6] ‐G (6.25; 12.5; 25.5 and 100 μM).
Inhibition of activity LTA 4H (El‐Naggar et al., 2017)
[6]‐G In vivo—Characterize the possible protective effects of [6]‐G on intestinal reperfusion injury
(I/R). Sprague–Dawley rats (N= 40)
Pretreatment with [6]‐G 25 mg/kg—intragastric route—3 days before reperfusion
Inhibition of the p38 MAPK
pathway
Inhibition of inflammatory
cytokines (TNF‐α,
IL‐1β, and IL‐6) and mediators
(NO/iNOS)
(Li et al., 2017)
Note. LTA 4H: leukotriene A 4 hydrolase; TNF‐α: tumor necrosis factor alpha; IL‐1β: interleukin 1 beta; IL‐6: interleukin 6; iNOS: inducible nitric oxide synthase; NO: nitric oxide; ALP: alkaline phosphatase; COX‐1:
cyclooxygenase 1; COX‐2: cyclooxygenase 2; CRC: colorectal cancer; IFN‐γ: interferon‐gamma; NF‐κB: nuclear factor kappa B; IκBα: inhibitor kappa B; interleukin 8 (IL‐8); SAA1: Serum amyloid A; STZ: streptozotocin;
VEGF: vascular endothelial growth factor; PGE2: prostaglandin E2; SAPK: stress‐activated protein kinase; JNK: Jun N‐terminal kinase; ROS: reactive oxygen species; ALP: alkaline phosphatase; MAPK: mitogen‐activated
protein kinase.
DE LIMA ET AL.9

of prostaglandin E2 synthase‐1 microsomal (mPGES1) and receptor
antagonism of its PGE2 product are considered potential therapeutic
targets for cancer cells expressing COX‐2 (Reader, Holt, & Fulton,
2011). Eventually, carcinogenesis is promoted by PGE 2 via GSK‐3β/
β‐catenin. Therefore, decreasing the level of PGE2 using mPGES‐1
inhibitors may be expected to show anticancer effect, and may have
a bright future as therapeutic agents (Ruana & So, 2014).
In a study by Li et al. (2013), human HuH7 hepatocyte cells were
stimulated with IL‐1βto establish an in vitro hepatic inflammatory
model, [6]‐gingerol attenuated IL‐1β‐induced inflammation and oxida-
tive stress in these cells. This was evidenced by the decrease in levels
of inflammatory factors IL‐6, IL‐8, and SAA1, in addition to suppres-
sion of ROS generation. Additionally, [6]‐gingerol reduced IL‐1β‐
induced positive regulation of COX‐2 as well as NF‐κB activity. The
protective effect of [6]‐gingerol with the IL‐1β‐induced inflammatory
response is similar to that of butylated hydroxytoluene, an ROS scav-
enger. Thus [6]‐gingerol could protect HuH7 cells against inflamma-
tory damage induced by IL‐1βby inhibiting the ROS/NF‐κB/COX‐2
pathway (Li et al., 2013).
In a similar fashion, Fan, Yang, and Bi (2015) investigated the
effect of [6]‐gingerol on the production of IL‐6 in osteoblasts. Results
revealed that [6]‐gingerol lowers the degree of inflammation in TNF‐α‐
treated MG‐63 cells. In addition, treatment with [6]‐gingerol increased
the activity of ALP enzyme in MG‐63 cells in a dose‐dependent man-
ner, whereas ALP activity was significantly reduced in response to
stimulation of TNF‐α. [6]‐Gingerol was thus reported to be a promis-
ing candidate for treating osteoporosis or bone inflammation (Fan
et al., 2015). The effect of ginger was even interesting in diabetic con-
ditions where EG standardized with 5% [6]‐gingerol attenuated retinal
microvascular changes in streptozotocin‐induced diabetic Wistar
albino rats. Additionally, orally administered [6]‐gingerol extract in dia-
betic rats reduced the levels of the proinflammatory marker TNF‐α
and expression of NF‐κB and vascular endothelial growth factor in
the retinal tissue of the (Dongare et al., 2016).
Several types of proinflammatory cytokines and chemokines are
produced during carcinogenesis. They influence tumor cell survival,
growth, mutation, proliferation, differentiation, and movement. Exper-
imental models of carcinogenesis indicate that these cytokines and
chemokines activate the NF‐κB transcription factor and TNF‐αas well,
which are implicated in tumor promotion (Aggarwal, 2003; Philip,
Rowley, & Schreiber, 2004). The protective effects of [6]‐gingerol on
proinflammatory cytokines such as TNF‐α,IL‐6, and IL‐1βand neutro-
phil infiltration in intestinal tissues with I/R injury was examined. Pre-
treatment with [6]‐gingerol significantly attenuated these cytokines in
a dose‐dependent manner, inhibited the expression of inflammatory
mediators, suppressed p38 phosphorylation, and activated NF‐κBby
negatively regulating MLCK expression (Li et al., 2017).
Chemoprevention based on dietary plants and/or phytochemicals
has emerged as an available and promising strategy for the control and
management of cancer with various mechanisms, including the
targeting of leukotriene A4 hydrolase (LTA4H; Badria, 1994; Houssen
et al., 2010; Surh, 2003). In this regard, [6]‐gingerol exhibited a wide
range of biochemical and pharmacological activities (Afzal, Al‐Hadidi,
Menon, Pesek, & Dhami, 2001; Ali, Blunden, Tanira, & Nemmar,
2008; Bode & Dong, 2011). LTA4H is a zinc dependent bifunctional
metalloenzyme with the activities of epoxide hydrolase and aminopep-
tidase. As an epoxide hydrolase, LTA4H catalyzes the last rate‐limiting
step in the leukotriene B 4 biosynthesis (LTB 4), a potent
chemoattractant that induces a vigorous inflammatory response, and
is related to the development of cancer (Chen, Wang, Wu, & Yang,
2004; Jeong et al., 2009). LTA4H inhibitory activity of [6]‐gingerol
derivatives was further reported by El‐Naggar et al. (2017). Docking
studies indicated that the phenolic –OH groups of [6]‐gingerol are
essential for inhibiting the activities of LTA4H, due to their chelation
with metallic zinc, a factor that may explain the inhibition of amino-
peptidase activity of the enzyme (El‐Naggar et al., 2017).
3.5 |Medicinal plants
Medicinal plants have been employed as a source for drug discovery
since 1805, when morphine became the first pharmacologically active
compound to be isolated, in a pure form, from a plant, although its
structure was not elucidated until 1923 (Salim, Chin, & Kinghorn,
2008). Natural drugs are used by a large portion of the population in
several countries to treat diseases such as inflammation, hypertension,
kidney problems, immune deficiency, and cancer (Cragg & Newman,
2013). Additionally, many of the current drugs are derived from plants
or their derivatives (Kinghorn, Pan, Fletcher, & Chai, 2011; Newman &
Cragg, 2012). Furthermore, polyphenols, secondary metabolites
widely diffused in the plant kingdom, are known to provide
protection against pathogens and parasites, and reduce the risk of
diseases induced by chronic and oxidative damage, including cancer
(Aboul‐Enein, Berczynski, & Kruk, 2013).
Use of crude and phytochemical extracts isolated from medicinal
plants is becoming more acceptable and preferable, possibly due to
the cost of production, availability, and accessibility and to lower tox-
icity in most cases. However, elucidation of molecular pathways and
side effects are crucial prior to clinical setting. In this respect, the chal-
lenge lies in the fact that phytochemicals are structurally complex, and
extraction of pure active compounds is extensively laborious. There-
fore, many synthetic drugs are inspired by the structure of active plant
molecules, highlighting the enormous potential in the development of
plant‐based drugs with therapeutic actions against cancer (Yehya
et al., 2017). Research findings have identified more than 5,000 indi-
vidual phytochemicals, and this number is steadily increasing due to
the introduction of current and efficient techniques of isolation and
characterization. These new agents are widely classified as phenolic
compounds, alkaloids, carotenoids, organosulfur, and nitrogen‐con-
taining compounds (Asif et al., 2016). Such molecules can act as anti-
oxidants, stimulate enzymatic activity, mimic hormones, interfere
with DNA replication, and protect cells from radiation and other
abnormal processes during tumorigenesis. In addition, studies have
also highlighted the synergistic effects of plant‐based medicinal com-
pounds as antiangiogenic agents when used in combination with other
antineoplastic drugs (Lachumy et al., 2013).
Cancer is a complex and multifactorial pathology; its etiology pre-
sumes genetic mutations that confer unlimited capacity for cell prolif-
eration, loss of response to growth inhibitory factors, evasion of
apoptosis, possibilities to invade other body tissues (metastases), and
production of new vessels (angiogenesis; Araújo & Galvão, 2010;
10 DE LIMA ET AL.

Hercos et al., 2014; INCA, 2014). Some phytochemicals have demon-
strated relatively low side effects and have even limited the incidence
of side effects associated with chemotherapeutic or antiangiogenic
agents (Wang et al., 2014). In this context, spices play an important
role as aromatic agents in the diet and are used in various regions of
the planet. A number of phytochemicals present in spices have been
recognized for having health promotion benefits and play a preventive
role in chronic diseases (Ferrucci et al., 2010; Kaefer & Milner, 2008).
Most of these phytochemicals exhibited promising broad spectrum
antiangiogenic activities in in vitro and in vivo models (American
Thoracic Society, 2000).
3.6 |Z. officinalle Roscoe and cancer
Ginger (Z. officinale) is one of the earliest domesticated spices in his-
tory. It is commonly used as a food additive (spices) and as a key com-
ponent in traditional herbal medicine, where its potential has been
intensely exploited in health benefits. Furthermore, ginger is consid-
ered safe as a herbal supplement by different regulatory authorities
(Butt & Sultan, 2011; Shukla & Singh, 2007; Al‐Suhaimi, Al‐Riziza, &
Al‐Essa, 2011). The bioactive components of ginger include volatile
oils, anthocyanins, tannins, and pungent phenolic compounds known
as gingerols, shogaols, and sesquiterpenes (Semwal, Semwal,
Combrinck, & Viljoen, 2015). Most of the research on antitumor activ-
ities of gingerols has focused on [6]‐gingerol, although little attention
has been paid to gingerols with longer unbranched alkyl side chains
(Semwal et al., 2015). Studies suggest that ginger and its pungent bio-
active components, which include gingerols and shogaols, can be used
in the prevention and treatment of cancer (Wang et al., 2014).
Experimental (in vitro/in vivo) and clinical trials revealed that EG
and [6]‐gingerol exhibit antiproliferative, antitumor, and anti‐invasive
effects via various mechanisms including NF‐κB, STAT3, Rb, MAPK,
PI3K, Akt, ERK, cIAP1, cyclin A, cyclin‐dependent kinase (Cdk), cathep-
sin D, and caspase‐3/7 (Prasad & Tyagi, 2015, 2015). Listed in Table 3
are the molecular mechanisms involved in tumor suppression, as well
as the mediators involved in cell signaling pathways in different types
of carcinomas and tumor cell lines. Yusof et al. (2009) evaluated the
anticancer effect of EG in rats with hepatic carcinoma, induced by a
choline deficient diet combined with ethionine. These researchers
found that animals treated with ginger showed a significant reduction
in the tumor size. In addition, ginger supplementation significantly
decreased MDA levels and increased catalase activity.
On the other hand, cancer metastasis consists of a complex cas-
cade of events that ultimately allow the escape of tumor cells and
the creation of ectopic environments (Yoon, Kim, & Chung, 2001).
However, the effect of [6]‐gingerol on metastasis in breast cancer cells
was not well understood. In this context, the effect of [6]‐gingerol on
adhesion, invasion, and motility in MDA‐MB‐231 human breast cancer
cells indicated that there is no effect on cell adhesion at concentra-
tions up to 5 μM but resulted in a 16% reduction when the concentra-
tion was increased to 10 μM. Additionally, increasing amounts of
[6]‐gingerol caused a concentration‐dependent decrease in cell migra-
tion and motility. Treatment of MDA‐MB‐231 cells with increasing
amounts of [6]‐gingerol caused a concentration‐dependent decrease
in cell migration and motility. Furthermore, the activities of matrix
metalloproteinase (MMP) 2 or MMP‐9, identified as possible media-
tors of invasion and metastasis in cancers, in MDA‐MB‐231 cells
decreased in a dose‐dependent manner upon treatment with
[6]‐gingerol (Lee et al., 2008).
Lin and colleagues examined the anticancer effects of [6]‐gingerol
on human colon cancer cell (LoVo) and observed a significant reduc-
tion in cell viability in a dose‐dependent manner. Results showed that
[6]‐gingerol significantly induces cell cycle arrest at the G2/M phase;
has little influence on the sub‐G1 phase; and decreases the levels of
cyclin A, cyclin B1, and CDK1. However, treatment with [6]‐gingerol
increased levels of negative cell cycle regulators p27Kip1 and
p21Cip1 and enhanced ROS levels and phosphorylation of p53. These
results highlight the importance of [6]‐gingerol in the treatment of
colon cancer (Lin et al., 2012). On the other hand, generation of ROS
induced by [6]‐gingerol is known to cause damage to DNA in cancer
cells (Oyagbemi et al., 2010; Lin et al., 2012). To investigate the molec-
ular mechanisms that mediate the apoptotic actions of [6]‐gingerol in
myeloid leukemia cells, Rastogi et al. (2014) selected chronic myelog-
enous leukemia (K562) and acute (U937) strains. Results indicated that
[6]‐gingerol induced generation of ROS in both cells, by inhibiting
mitochondrial respiratory complex I, and triggered cell death mediated
through an increase in miR‐27b expression and DNA damage. These
data clearly indicate that treatment with [6]‐gingerol alters the cellular
oxidant status; induces generation of mitochondrial ROS, leading to
G2/M cell cycle disruption; and decreases protein expression (cyclin
B1, Cdk1, Cdc25B, and Cdc25C), associated with the phases of the
cycle (Rastogi et al., 2014).
Karna and coworkers similarly showed that EG exhibits substan-
tial growth‐inhibitory effect and induced death in a panel of prostate
cancer cells. Additionally, EG reduced cell cycle progression,
decreased the capacity to reproduce, and initiated a caspase‐driven,
mitochondrially mediated apoptosis (Karna et al., 2012). Recently,
the effect of [6]‐gingerol on human papilloma virus positive cervical
cancer cells (HeLa, CaSki, and SiHa) was evaluated. Results showed
that [6]‐gingerol induces inhibition of cell viability in lineages tested
in dose and time‐dependent fashion. At a concentration of 50 μM,
[6]‐gingerol inhibited the growth and proliferation of HeLa (20%),
CaSki (23%), and SiHa (28%) cells after 24 hr of treatment, indicating
apoptotic cell death. In nontumor cells HACAT, HEK293, and human
peripheral blood monocytes (PBMCs), [6]‐gingerol at a dose of
50 μM did not induce cytotoxicity in normal lineages (Rastogi et al.,
2015). Research findings indicated that restoration of the p53 func-
tion is critical for effective therapeutic targeting and management of
cervical cancer (Horner, Defilippis, Manuelidis, & Dimaio, 2004).
Rastogi et al., 2015 reported that [6]‐gingerol inhibits the proteasome
and induced p53 reactivation and apoptotic cell death in cervical can-
cer cells. [6]‐Gingerol additionally potentiated the cytotoxic effects of
cisplatin, which is a traditional chemotherapeutic agent. These results
suggest that [6]‐gingerol may be used as a single agent or in combina-
tion with conventional chemotherapeutic drugs and is presented as a
promising therapeutic strategy for the management and treatment of
cervical cancers (Rastogi et al. (2015).
Transcriptional silencing of human papilloma virus, E6, and E7
oncoproteins is known to inhibit cervical cancer cell proliferation
(Tan, De Vries, Van Der Zee, & De Jong, 2012). [6]‐Gingerol did not
DE LIMA ET AL.11

TABLE 3 Antitumor effect of ginger extract (EG) and/or biologically active phytochemical component [6]‐gingerol ([6]‐G)
Form of use
Method of study Mechanism of action
EG and/or [6]‐G ReferenceDose or concentration
[6]‐G In vitro—to examine the effects of [6]‐G on adhesion, invasion, and motility
in MDA‐MB‐231 (human breast cancer) to [6]‐G (0, 2.5, 5, and 10 μM)
Decreases activity of MMP‐2 and MMP‐9 (Lee, Seo, & Kim, 2008)
EG In vivo—Male Wistar rats (N= 6) ginger effect on ethionine‐induced
hepatocarcinogenesis
Induction of hepatic cancer with ethionine—15 weeks—intraperitoneal route
Food or olive oil controls; EG (100 mg/kg); choline deficient diet (CDE) + 0.1%
ethionine; ginger + CDE. 8 weeks—oral
Group treated with ginger:
Decrease tumor incidence
Increase CAT
Decrease MDA
(Yusof, Ahmad, Sulaiman, & Murad, 2009)
[6]‐G In vitro—To explore the mechanisms of [6]‐G in HeLa (human cervical carcinoma)
[6]‐G (25, 50, 75, 100, 125, 150, and 175 μg/ml)
Induction of apoptosis
Upregulation of TNF‐αand Bax and
citocromo c. Downregulation of
NF‐κB, AKT, and Bcl2
(Chakraborty et al., 2012)
EG In vitro—To investigate cytotoxic and apoptotic capacity in human MPC11
(myeloma) and murine WiDr (colorectal cancer) cells. Administration of
EG (500–7.81 μg/ml)
Induction of apoptosis
Increases p53
(Ekowati et al., 2012)
EG In vitro—Antiproliferative potential of EG (0.0, 0.025, 0.05, 0.1, 0.15, and
0.2 mg/ml) in breast cancer cell lines (MCF‐7 and MDA‐MB‐231) and
lineage epithelial cells (MCF‐10A). Assays viability (200 × 10
3
), comet
(1 × 106), apoptosis (2 × 10
4
) cells/ml
Increases apoptosis, Bax, caspases‐3,
PARP, IκBα
Decreases NF‐κB, Bcl2, BclX, Mcl‐1,
survivina, cyclin D1, Cdk‐4, and hTERT
(Elkady, Abuzinadah, Baeshen, & Rahmy, 2012)
EG In vitro—Exposure of prostate cancer strains, LNCaP, C4‐2, C4‐2B, DU145,
PC‐3, and PrEC (normal) to EG (1; 10; 100; and 1,000 μg/ml) for cell viability
Flow cytometry: EG‐treated PC‐3 line (50; 100; 250; 500; and 1,000 μg/ml)
Western blot, immunohistochemistry, Caspase3/7 activity: PC‐3 to EG (250 μg/ml)
Cell cycle stop G1 and S
Increases sub‐G1 population, p21, JC‐1, BAX,
cytochrome c mitochondrial, PARP cleavage,
and caspase‐3
Decreases Ki67, cyclin D1, E, Cdk‐4, and Bcl2
(Karna et al., 2012)
EG In vivo—Male nude mouse (N= 6) xenograft PC‐3.
Induction prostate cancer (PC‐3/1 × 10
6
)—subcutaneous route
Administration of EG (100 mg/kg—8 weeks)—oral
Decreases Ki67, cyclin B, cyclin D1, and cyclin E
Increases p21, caspase‐3, and PARP
(Karna et al., 2012)
[6]‐G In vitro—Investigating the antitumor effects of [6]‐G on LoVo (4 × 10
4
) to [6]‐G
(0, 5, 10, and 15 μg/ml) human colon cancer cells (LoVo)
Stops cell cycle G2/M phase
Decreases cyclin A, B1, and CDK1
Increase p27
Kip1
and p21
Cip1
(Lin, Lin, & Tsay, 2012)
[6]‐G In vitro—To examine the effect of [6]‐G on metastases of pancreatic cancer and to
investigate intracellular signaling pathways involved in PANC1 (1 × 10
4
) to [6]‐G
(0, 5, 10, 15, or 20 μM)
Increase TER, protein levels TJ, ZO‐1, accludin,
and E‐cadherin
Decreases MMP‐2, ‐9, claudin‐4, NF‐κB/Snail,
and ERK
(Kim & Kim, 2013)
EG In vitro—Exposure of B164A5 melanoma cell line (1 × 10
3
cells) to EG
(0, 20, 60,
80, and 100 μg/ml)
Increases apoptosis (Danciu et al., 2015)
EG In vitro—Exposure of U251 cell line (1 × 104) to EG, viability (0, 50, 100, 150,
and 200 μg/ml); 0.75 μg/ml
Increases cytochrome c mitochondrial, Bax
ratio: Bcl‐2, caspases‐3, ‐9, PARP‐1 cleavage,
p53, and p21
(Elkady, Hussein, & Abu‐Zinadah, 2014a)
(Continues)
12 DE LIMA ET AL.

TABLE 3 (Continued)
Form of use
Method of study Mechanism of action
EG and/or [6]‐G ReferenceDose or concentration
Decreases nuclear NF‐κBp65, survivin, XIAP,
and cyclin D1
EG In vitro—HCT116 human colorectal cancer cell line exposure
(5 × 104) to EG,
viability (0, 50, 75, 100, and 125 μg/ml); markers (0.75 μg/ml)
Increases cytochrome c mitochondrial, Bax ratio: Bcl‐2,
caspases‐3, −9,
PARP‐1 cleavage, p53, p21, and p27
Decreases Bcl2, BclX, Mcl‐1, survivin, XIAP, cyclin D1,
Cdk‐4, and c‐Myc
(Elkady, Hussein, & Abu‐Zinadah, 2014b)
[6]‐G In vitro—Exposure of human glioblastoma U87 line (1 × 10
5
cells) to [6]‐G
Viability/apoptosis (10–100 μM)
Markers/modulation (0–50 μM)
Increases ROS, DR5, p53, bid cleavage, and BAX
Decreases expression survivin, c‐FLIP, Bcl2, and XIAP
(Lee, Kimb, Jungc, Leea, & Parkd, 2014)
[6]‐G In vitro—To evaluate the antiproliferative capacity in tumoral lines
of acute and chronic myeloid leukemia to [6]‐G (0, 10, 25, 50,
100, and 200 μM)
To analyze the apoptotic mechanisms of [6]‐G in LMC (K562) and
AML (U937) to [6]‐G (50 μM)
Induction of caspase‐3 activity
PARP cleavage
Generation of mitochondrial ROS
G2/M cell cycle disruption
Decreases expression of proteins (cyclin B1, Cdk1,
Cdc25B, and Cdc25C)
Increases expression of miR27b
(Rastogi et al., 2014)
[6]‐G Ex vivo—Investigating the effects of [6]‐G on PBMCs cells, obtained
from patients with AML (N= 40); LMC (N= 7) and healthy (N=6)
to [6]‐gingerol (50 μM)
Induction of apoptosis in AML and CML groups (Rastogi et al., 2014)
[6]‐G In vivo—Mouse nude (N= 24). K562‐induced xenotransplantation
tumor model (3 × 10
6
). Administration [6]‐G (5 mg/kg)—45
alternate days—intraperitoneal
Decreases PCNA, Bcl2, BclXL, and XIAP
Increases Bax, Bak, cleavage of PARP, and activation of
caspase‐3
(Rastogi et al., 2014)
[6]‐G In vitro—Cytotoxic effects on human tumor cell lines SW‐480,
HCT 116 (5 × 10
3
), and normal murine colon (5 × 10
4
) to [6]‐G
(5, 10, 25, 50, 100, 200, and 300 μM) primary cells, evidence
possible mechanisms of action in (SW‐480)
Activation of caspases‐8, ‐9, ‐3, ‐7, and cleavage of
PARP
Inhibition via ERK1/2, JNK, and AP‐1
(Radhakrishnan et al., 2014)
EG In vitro—Investigating the effects of EG on human pancreatic
cancer strains Panc1, AsPC1, BxPC3, CAPAN2, CFPAC1,
MIAPaCa2, SW1990, and Panc02 murine pancreatic cancer
cell employing EG (SSHE)—25, 50, 100, and 200 μg/ml
Cell cycle arrest at the G0/G1 phase
Induction of autose
Increases ROS
(Akimoto, Lizuka, Kanematsu,
Yoshida, & Takenaga, 2015)
E G In vivo—C57BL/6 male mice (N= 8).
Induction of pancreatic cancer Panc02‐Luc‐ZsGreen
(5 × 10
5
cells)—intraperitoneal
Decreases tumor incidence
(Akimoto et al., 2015)
(Continues)
DE LIMA ET AL.13

TABLE 3 (Continued)
Form of use
Method of study Mechanism of action
EG and/or [6]‐G ReferenceDose or concentration
Administration of EG (SSHE; 80 mg/kg—20 consecutive days
immediately after induction)—intraperitoneal
[6]‐G In vitro—Human HepG2 tumor line
Exposure of HepG2 tumor lines to[6]‐G (0.01, 0.1, 0.2, 0.3,
0.4, and 0.5 nM)
Induces apoptosis
Cycle stop: Go/G1, S—24 hr; G2/M—48 hr
Increases ROS
Downregulation of FASN
(Impheng et al., 2015)
EG In vitro—Exposure of line derived human Burkitt Raji lymphoma (1 × 10
6
cells) to EG (0.1%, 0.01%, and 0.001%)
Decreases viability (Parvizzadeh et al., 2014)
[6]‐G In vitro—To explore the mechanism of action of [6]‐G (50 μM) in human
cervical cancer cells positive for HPV (HeLa, CaSki, and SiHa)
Induction of apoptosis
Reactivation of p53 independent of inhibition of the
oncoprotein (E6/E7) in HeLa and CaSki lines.
Increases p53, P21, and ROS
Induction of G2/M cell cycle arrest
(Rastogi et al., 2015)
[6]‐G In vivo—Tumor induction (xenotransplantation) employing HeLa cell
(3 × 10
6
) in nude mouse (N=6)—intraperitoneal route
Administration of [6]‐G (2.5 and 5.0 mg/kg)—45 alternate days
Induction of apoptosis
Reactivation and increase of p53 levels
(Rastogi et al., 2015)
EG In vitro—Exposure of HT29 colorectal tumor cell line (1 × 10
6
cells)
to EG (2–10 mg/ml)
Induction of apoptosis
Downregulation of KRAS, ERK, AKT, Bcl‐xL,
and p65 NF‐κB
Upregulation caspase‐9
(Tahir et al., 2015)
[6]‐G In vitro—Exposure of the HeLa lines to [6]‐G (100 and 200 μM), to
evaluate the antitumor potential and its synergy with 5FU drugs (50 μM); Ptx.
Cell cycle stop G0/G1
Regulation of apoptosis in the PI3K/
AKT/MAPK/mTOR pathway
Synergy with the 5FU and Ptx antineoplastic
drugs led to 83.2% and 52% inhibition
(F. Zhang et al., 2017)
Note. ROS: reactive oxygen species; MMPs: matrix metalloproteinases; MDA: malondialdehyde; CAT: catalase; TNF‐α: tumor necrosis factor alpha; NF‐κB: nuclear factor kappa β; CDKs: cyclin‐dependent kinases; JC‐1:
5,5′, 6,6′‐tetrachloro1,1′, 3,3′‐tetraethylbenzimidazolecarbocyanine iodide; PARP: Poly (ADP‐ribose) polymerase; TER: transepithelial electrical resistance; TJ: tight junction; ZO‐1: zonula occludens; XIAP: X‐linked chro-
mosome to apoptosis inhibitor; DR5: death receptor 5; c‐FLIP: FLICE inhibitor protein; AML: acute myeloid leukemia; CML: chronic myelogenous leukemia; FASN: fatty acid synthase enzyme; PI3‐K: phosphatidylinositol
3‐kinases; 5FU: 5‐fluorouracil; Ptx: paclitaxel; ERK: extracellular signal‐regulated kinase; JNK: Jun N‐terminal kinase; HPV: human papilloma virus.
14 DE LIMA ET AL.

affect the expression of E6 and E7 levels in HeLa and CaSki cells; how-
ever, p21 levels were significantly increased in both cells, which might
explain the involvement of p53 in the apoptotic process in these cells.
In addition, [6]‐gingerol increased ROS production in cervical cancer
cells. Generation of [6]‐gingerol‐induced intracellular ROS leads to
apoptotic cell death, DNA damage, and p53/p21‐mediated G2/M cell
cycle arrest (Rastogi et al., 2015). Furthermore, animals treated with
[6]‐gingerol (2.5 and 5.0 mg/kg body weight) for 6 weeks showed a
significant reduction in tumor volume (about 65%). Consistent with
the in vitro results, proteasomal inhibition and increased p53 levels
were observed in the xenografts of treated mice. Expression of cell
cycle regulators and other apoptotic markers were also observed
according to in vitro studies. Potent antiproliferative effect of [6]‐
gingerol in vivo is mediated by proteasomal inhibition and reactivation
with p53, leading to inhibition of proliferation and induction of apo-
ptotic cell death (Rastogi et al., 2015). [6]‐Gingerol was found to
reduce the viability of HeLa (human cervical carcinoma) cells as shown
by morphological changes in cells. HeLa cells treated with [6]‐gingerol
showed altered nuclear and cellular morphology, cell shrinkage, and
membrane blebbing, which are characteristics of apoptotic cell death.
Additionally, an increase in chromatin condensation and fragmentation
of HeLa cells was observed with increased dose of [6]‐gingerol during
treatment (Chakraborty et al., 2012).
Metastasis is a multistep process involving invasion and migration
and is the leading cause of death in cancer patients. In cancer, degra-
dation of extracellular matrix and basement membrane through activa-
tion of MMPs and remodeling of tissue via loss, TJ, promotes
migration of tumor cells. The effect of [6]‐gingerol on transepithelial
electrical resistance and paracellular permeability of pancreatic cancer
cells was investigated using the PANC‐1 cell line. Results indicated
that [6]‐gingerol restores TJ formation and suppresses paracellular
permeability compared with that of untreated cells. In addition, it sig-
nificantly increased transepithelial electrical resistance and decreased
claudin‐4 and MMP‐9. Furthermore, [6]‐gingerol enhanced TJ protein
levels, including zonula occludens (ZO‐) 1, occludin, and E‐cadherin,
which is correlated with decreased paracellular flux and MMP‐2 and
MM‐9 activity. Treatment with [6]‐gingerol suppressed nuclear trans-
location of NF‐κB/Snail by downregulation of ERK pathway. These
results suggest that [6]‐gingerol can suppress the invasive activity of
PANC‐1 cells (Kim & Kim, 2013).
A study by Elkady and colleagues indicated that human breast
cancer cell lines MCF‐7 and MDA‐MB‐231 are considerably more sen-
sitive to growth suppression than the normal mammary line MCF‐10A
when treated with EG. Treatment with EG (0.1 mg/ml) caused a 25‐
and 20‐fold increase in the percentage of labeled apoptotic cells in
MCF‐7 and MDA‐MB‐231, respectively. On the other hand, treatment
with a 0.2 mg/ml dose of EG triggered a 40‐and 30‐fold increase in
apoptosis in MCF‐7 and MDA‐MB‐231, respectively. The antiprolifer-
ative potential of ginger can be attributed to its induction of apoptosis
by increasing the Bax/Bcl‐2 ratio. Moreover, ginger‐dependent
growth inhibitory mechanisms may involve, at least in part, the down-
regulation of major cell molecules, including NF‐κB, Bcl‐X, Mcl‐1,
survivin, cyclin D1, CDK‐4, proto‐oncogene proteins (c‐Myc), hTERT,
and upregulation of IκBαand p21. As the inhibition of c‐Myc and
hTERT is a specific target in cancer therapy, EG might be a good
candidate as a chemopreventive or therapeutic agent for breast cancer
(Elkady et al., 2012).
Similarly, gingerol was found to function as a sensitizing agent to
induce tumor necrosis factor‐related apoptosis inducing ligand
(TRAIL)‐mediated apoptosis in glioblastoma cells, which are resistant
to TRAIL‐induced apoptosis, by TRAIL signaling (Lee et al., 2014). This
effect was evidenced by elevated expression level of the death recep-
tor 5, decreased expression of antiapoptotic proteins such as survivin,
cFLIP, Bcl2, and X‐linked chromosome to apoptosis inhibitor (XIAP),
and by increased levels of proapoptotic proteins including Bax and
Bid, caused by generation of ROS. These results suggest that gingerol
could be used as an antitumor agent that may serve in combination
therapies with TRAIL in patients with TRAIL‐resistant glioblastoma
(Lee et al., 2014).
Treatment of human glioblastoma cells (U251) with EG reduced
cell viability, induced apoptosis mediated by cytochrome c‐mitochon-
drial release, increased Bax:Bcl‐2 ratio and caspase‐3 activity, and
caused PARP1 cleavage. In addition, EG decreased the expression
levels of nuclear NF‐κBp65, survivin, XIAP, and cyclin D1, and
increased expression levels of proapoptotic proteins p53 and p21
(Elkady et al., 2014a). On the other hand, treatment of human
HCT116 (colorectal) cancer cells with EG caused morphological and
biochemical characteristics of apoptotic cell death. Induction of apo-
ptosis was associated with mitochondrial cytochrome c release,
increased Bax:Bcl2 ratio, activation of caspase‐3 and ‐9, and
PARP cleavage. Furthermore, EG (a) decreased the expression levels
of antiapoptotic proteins including Bcl2, BclX, Mcl‐1, survivin,
and XIAP; (b) elevated expression levels of the oncosuppressive
proteins, p53, p21, and p27; (c) reduced the expression of cyclin
D1 and cyclin/Cdk‐4; and (d) decreased expression of c‐Myc (Elkady
et al., 2014b).
In a recent publication, Danciu and coworkers showed that
EG exhibits antiproliferative and proapoptotic activity in murine
melanoma B164A5 cell line (Danciu et al., 2015). On the other hand,
research findings indicated a high cytotoxic effect of EG against Raji
cells derived from human (non‐Hodgkin's) Burkitt's lymphoma
(Parvizzadeh et al., 2014). In a similar fashion, Rastogi et al. (2014)
studied the effects of [6]‐gingerol on myeloid leukemia cells
in vitro and in vivo. These researchers found that [6]‐gingerol, con-
centration and time dependently, impedes propagation of myeloid
leukemia cell lines and does not affect the normal peripheral blood
mononuclear cells. Additionally, and using U937 and K562 cell lines,
[6]‐gingerol prompted generation of ROS through inhibition of
mitochondrial respiratory complex I, which enhanced the expression
of oxidative stress response‐linked microRNA miR‐27b and
DNA damage. The increased expression of miR‐27b inhibits the
peroxisome proliferator‐activated receptor γ, which causes inhibition
of the inflammatory cytokine gene expression linked with the onco-
genic NF‐κB pathway. On the other hand, increased DNA damage
leads to G2/M cell cycle arrest. In short, the [6]‐gingerol‐induced
death in myeloid leukemia cells triggered by ROS and mediated by
an elevation in miR‐27b expression and DNA damage (Rastogi
et al., 2014).
Research findings indicated that natural compounds can induce
inhibition of primary leukemia cells (Sharif et al., 2012). Rastogi et al.
DE LIMA ET AL.15

(2014) demonstrated that [6]‐gingerol affects the growth of peripheral
blood mononuclear cells PBMCs obtained from 40 patients with acute
myeloid leukemia (AML), seven patients with chronic myeloid leuke-
mia (CML), and six healthy donors. Each one of these primary cultures
of leukemia was exposed to 50 μM of [6]‐gingerol for 48 hr, and
annexin V (apoptosis marker) binding was measured by means of flow
cytometry alone. Results revealed that the optimal effects of [6]‐
gingerol on induction of apoptosis in AML and CML cells were
achieved by 48 hr posttreatment. On the other hand, [6]‐gingerol‐
mediated apoptosis was observed in 30 of the 40 AML samples and
six of the seven CML tested samples. In addition, treatment with [6]‐
gingerol did not markedly affect the viability of normal PBMCs. These
results suggest that [6]‐gingerol could be effective in inducing apopto-
sis in both AML and CML cells. It is well known that oxidative stress
due to accumulation of ROS causes changes in the expression of
miRNA in several cell types (Lin et al., 2009; Simone et al., 2009; Wang
et al., 2010); Lee et al., 2009). Rastogi et al. (2014) evaluated the
changes in miRNA expression in K562 and U937 myeloid leukemia cell
lines after [6]‐gingerol‐induced accumulation of ROS. Results showed
that miR27b expression was increased 4.8 and 4.9‐fold in K562 and
U937 cells treated with [6]‐gingerol, respectively, compared with
untreated cells. This indicates that miR27b may be related to
proapoptotic effects of [6]‐gingerol, suggesting that miR27b expres-
sion is critical in mediating its proapoptotic effects in leukemia cells.
To further validate the results obtained in vitro, it was shown that
[6]‐gingerol could inhibit the development of tumors in a murine
xenograft tumor model in vivo. Results revealed that treatment with
[6]‐gingerol significantly reduced antiapoptotic proteins such as prolif-
erating cell nuclear antigen, Bcl2, BclXL, and XIAP and increased
proapoptotic proteins including Bax, Bak, and PARP cleavage and acti-
vation of caspase‐3. However, [6]‐gingerol did not negatively affect
hematological parameters or body weights, indicating its chemothera-
peutic potential (Rastogi et al., 2014).
[6]‐Gingerol exhibited toxicity in both SW‐480 and HCT116
tumor cells in a dose‐dependent manner, with prominent effect at
higher concentrations with IC
50
values of 205 ± 5 and 283 ± 7 μM,
respectively; cell viability in normal cells remained unchanged. These
results suggest the specificity of [6]‐gingerol in inducing cytotoxicity
in cancer cells without being toxic to normal cells, even at higher con-
centrations. In SW‐480 cells treated with [6]‐gingerol, significant
cleavage of procaspase‐8 and ‐9 to their active fragments p43/41,
p35/37, respectively, was observed. Activation of effector caspase‐3
and ‐7 was also induced by [6]‐gingerol in a dose‐dependent manner,
with cleavage of procaspase‐3 and ‐7a to their respective active
fragments p17/19 and p20. Similarly, cleavage of the PARP protein,
which is a caspase‐3 substrate, has also been observed confirming a
caspase‐mediated apoptosis (Radhakrishnan et al., 2014).
Recently, Akimoto et al. (2015) examined the anticancer activity
of EG against pancreatic cancer cells in vitro/in vivo and investigated
its potential mechanism. These researchers observed that tumor
growth and cell viability in pancreatic cells are mainly mediated
through autose by ROS, a way of characterizing cell death. Similarly,
treatment of Panc1 cells with EG for 20 hr resulted in a cell cycle
arrest at the G0/G1 phase. Normal cells, such as HUVEC and
HPAEpiC, were more resistant to EG compared with Panc cells,
revealing EG selectivity. In the later stages of cell death of Panc1
cells, focal rupture of the plasma membrane and shrinkage of the
nucleus were observed. EG significantly increased the LC3‐II/LC3‐I
ratio, an indicator of autophagosome formation, in a dose‐and
time‐dependent manner. In Panc‐1 cells, EG additionally decreased
levels of SQSTM1/p62 protein, one of the specific substrates
degraded through the autophagic‐lysosomal pathway. Moreover,
EG activated MAPK, a positive regulator of autophagy and
inhibited mTOR, a negative autophagous regulator. Inhibitors of 3‐
methyladenine and chloroquine autophagy partially prevented cell
death. Morphologically, cells treated with EG showed massive
vacuolization of the cytoplasm approximately 24 hr after treatment.
These cytoplasmic vacuoles were probably autophagosomes because
the GFP‐LC3 tip appeared after treatment with EG. Changes in the
generation of ROS, following the treatment of Panc‐1 cells with
EG, showed a biphasic pattern. In the initial stages (approximately
10 hr), generation of ROS was inhibited by EG. However, prolonged
treatment resulted in a robust increase in the generation of ROS and
an increase in mitochondrial superoxide production. These results
suggest the generation of ROS as a cause of EG‐induced cell death
(Akimoto et al., 2015).
Obesity is associated with the metabolic syndrome and the dys-
regulation of new fatty acid synthesis, leading to numerous conse-
quences, including tumorigenesis and tumor progression (Ameer,
Scandiuzzi, Hasnain, Kalbacher, & Zaidi, 2014). Numerous studies
have focused on the effect of natural polyphenols in reducing hepatic
fat accumulation, overweight, and obesity to reduce the risk of carci-
nogenesis without disrupting food appetite (Figarola et al., 2013;
Huang et al., 2014; Kang et al., 2013). In order to confer rapid prolif-
eration and survival, cancer reorients acetylcoenzyme A into oxidative
phosphorylation to develop overexpression of the de novo synthesis
pathway of fatty acids (Rodriguez‐Enriquez, Marin‐Hernandez,
Gallardo‐Perez, & Moreno‐Sanchez, 2009). Enzymes that participate
in the synthesis of new fatty acids are regulated or constitutively
expressed in most types of cancer cells (Ferreira, 2010; Hopperton,
Duncan, Bazinet, & Archer, 2014; Zaidi et al., 2013). In this regard,
Impheng et al. (2015) demonstrated that [6]‐gingerol reduces fatty
acid synthesis, resulting in mitochondrial dysfunction and induction
of cell death in HepG2 cells. In addition, [6]‐gingerol induced inhibi-
tion of fatty acid synthase (FASN) expression, indicating FASN is a
major target of [6]‐gingerol inducing apoptosis in HepG2 cells medi-
ated by increased generation of ROS. Furthermore, a decrease of
fatty acid levels and initiation of apoptosis were restored by inhibition
of acetyl‐CoA carboxylase activity. This suggests that accumulation of
malonyl‐CoA level could be the major cause of apoptotic induction of
[6]‐gingerol in HepG2 cells. The findings of [6]‐gingerol as a novel
FASN inhibitor provide a potential perspective on anticancer and lipo-
genesis inhibitor treatments to protect obesity‐induced carcinogene-
sis (Impheng et al., 2015). Findings collectively suggest that that
treatment of HeLa cells with [6]‐gingerol caused growth inhibition,
cell cycle arrest at G0/G1 phase, and apoptosis. In addition, it (a)
decreased the expression of cyclin (A, D1, E1); (b) slightly decreased
CDK‐1, p21 and p27; and (c) increased Bax/Bcl‐2 ratio, release of
cytochrome c, and cleavage of caspase‐3, ‐8, ‐9, and phosphoribosyl
pyrophosphate (F. Zhang et al., 2017).
16 DE LIMA ET AL.

4|CONCLUSIONS
Use of conventional therapies such as natural products, extracted
from plants, in the fight against diseases such as cancer has attracted
the attention of the scientific and medical communities due to their
lesser side effects and cost. In this context, [6]‐gingerol, a flavonoid
antioxidant and the main active constituent of fresh ginger, has been
recognized and employed as an alternative drug in treating different
cancers, alone or in combination with other chemotherapeutic drugs.
It displays important antioxidant and/or anti‐inflammatory effects that
could be employed in preventing and treating cancer. Data obtained
from experimental (in vitro/in vivo) and clinical studies reveal that
EG and/or [6]‐gingerol exhibit antiproliferative, antitumor, anti‐inva-
sive, and anti‐inflammatory effects in chronic diseases and carcinoma.
[6]‐Gingerol exerts cytotoxic effects on various cancer cell lines at
0.01 nM to 300 μM, whereas in mice, it exhibited anticancer effects
at 5, 25, and 45 mg/kg (i.p.).
These natural compounds exert their effect through different
mechanisms and cell signaling pathways. In short, the use of crude
and phytochemical extracts isolated from medicinal plants is becoming
increasingly common and acceptable; however, identification and
understanding of molecular pathways and mediators are crucial in elu-
cidating the protective or therapeutic potential, as well as dose
response, toxicity, and biological response. In summary, this review
reveals that [6]‐gingerol can be an important complementary medicine
for prevention and treatment of different types of cancers, owing to
its natural origin, safety, and low cost relative to synthetic cancer
drugs. However, further studies are needed on this natural compound.
Additionally, because most of the results and conclusions in this
review came from in vitro and in vivo studies, more work that involves
different pharmacokinetic parameters are recommended in the future
before this substance becomes a prescribed drug. Moreover, develop-
ment of standardized extract or dosage could also be pursued in
clinical trials.
CONFLICT OF INTEREST
The authors do not have any conflict of interest to disclose.
LIST OF ABBREVIATION
5′NT 5′‐nucleotidase
5FU 5‐fluorouracil
ACC Acetyl‐CoA carboxylase
AFB1 Aflatoxin B1
Akt/PKB Protein kinase B
ALP Alkaline phosphatase
ALT Alanine aminotransferase
AML Acute myeloid leukemia
AP Acid phosphatase
AP‐1 Acid phosphatase 1
A‐SAA Serum amyloid A
AST Aspartate aminotransferase
Aββ‐amyloid
Bax (B‐cell lymphoma)‐associated X
Bcl2 B‐cell lymphoma 2
BHT Butylated hydroxytoluene
BJ Foreskin fibroblasts
Caco2 Human colon adenocarcinoma
CAT Catalase
Cdk‐4 Cyclin‐dependent kinase 4
c‐FLIP FLICE inhibitor protein
CML Chronic myelogenous leukemia
c‐Myc Proto‐oncogene proteins
COX Cyclooxygenase
COX‐1 Cyclooxygenase 1
COX‐2 Cyclooxygenase 2
CRC Colorectal cancer
CRP C‐reactive protein
DMH 1,2‐dimethylhydrazine
DOX Doxorubicin
DR5 Death receptor 5
ECH Enoyl‐CoA hydratase
EG Ginger extract
ERK Extracellular signal‐regulated kinase
FASN Fatty acid synthase
FoxOs Forkhead box protein Os
G6Pase D‐glucose‐6‐phosphate phosphohydrolase
GFP‐LC3 Green fluorescent protein‐light chain 3
GGT Gamma‐glutamyl transferase
GPx Glutathione peroxidase
GPx‐1 Phosphatase glutathione peroxidase 1
GR Glutathione reductase
GSH Glutathione
GSK3βGlycogen synthase kinase 3 beta
GSSG Glutathione disulfide
GST Glutathione S transferases
GSTP1 Glutathione S‐transferase P1
HIF‐1αHypoxia‐inducible factor 1‐alpha
HO‐1 Heme oxygenase 1
HPV Human papilloma virus
hTERT Human telomerase reverse transcriptase
IEC6 Intestinal epithelial cell line 6
IFN‐γInterferon‐gamma
IL‐1 Interleukin 1
IL‐1βInterleukin 1 beta
IL‐6 Interleukin 6
IL‐8 Interleukin 8
INCA Instituto Nacional de Câncer José
Alencar Gomes da Silva
iNOS Inducible nitric oxide synthase
I/R Ischemic–reperfusion injury
IκBαInhibitor kappa B
JAK Janus associated kinases
JNK Jun N‐terminal kinase
LDH Lactate dehydrogenase
LPS Lipopolysaccharide
LTA4H Leukotriene A4 hydrolase
LTB 4 Leukotriene B 4 biosynthesis
MAPK Mitogen‐activated protein kinase
DE LIMA ET AL.17

Mcl‐1 Myeloid cell leukemia 1
MDA Malondialdehyde
MG‐63 Human osteoblast‐like cells
MLCK Myosin light‐chain kinase
MMP‐2 Matrix metalloproteinase 2
MMP‐9 Matrix metalloproteinase 9
mPGES Prostaglandin E2 synthase‐1 microsomal
NF‐κB Nuclear factor kappa beta
NO Nitric oxide
Nrf2 Nuclear erythroid 2 related to factor 2
p38 Protein 38
p53 Protein 53 (tumor)
PARP Poly (ADP‐ribose) polymerase 320
PBMCs Peripheral blood monocytes
PCNA Proliferating cell nuclear antigen
PG Prostaglandin
PGE Prostaglandin E
PGE2 Prostaglandin E2
PI3‐K Phosphatidylinositol 3‐kinase
PLC‐γ1 Phospholipase C gamma 1
PPARγPeroxisome proliferator‐activated receptor γ
PRPP Phosphoribosyl pyrophosphate
Ptx Paclitaxel
ROS Reactive oxygen species
SAPK Stress‐activated protein kinase
SDH Sorbitol dehydrogenase
SOD Superoxide dismutase
STAT Signal transducer and activator of transcription
STZ Streptozotocin
TER Transepithelial electrical resistance
TJ T ight junction
TNF‐αTumor necrosis factor alpha gene
TRAIL Tumor necrosis factor‐related apoptosis inducing ligand
VEGF Vascular endothelial growth factor
XIAP X‐linked chromosome to apoptosis inhibitor
ORCID
Muhammad Torequl Islam http://orcid.org/0000-0003-0034-8202
Siddhartha Kumar Mishra http://orcid.org/0000-0003-1627-1377
Mohammad S. Mubarak http://orcid.org/0000-0002-9782-0835
REFERENCES
Aboul‐Enein, Y., Berczynski, H., & Kruk, I. P. (2013). Phenolic compounds:
The role of redox regulation in neurodegenerative disease and cancer.
Mini Reviews in Medicinal Chemistry,13(3), 385–398.
Afanas, I. (2014). New nucleophilic mechanisms of ROS‐dependent epige-
netic modifications: Comparison of aging and cancer. Aging and Disease,
5(1), 52–62.
Afzal, M., Al‐Hadidi, D., Menon, M., Pesek, J., & Dhami, M. S. (2001).
Ginger: An ethnomedical, chemical and pharmacological review. Drug
Metabolism and Drug Interactions,18, 159–190.
Aggarwal, B. B. (2003). Signalling pathways of the TNF superfamily: A
double‐edged sword. Nature Reviews Immunology,3(9), 745–756.
Aggarwal, B. B., & Gehlot, P. (2009). Inflammation and cancer: How friendly
is the relationship for cancer patients? Current Opinion in Pharmacology,
9(4), 351–369.
Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., & Sethi, G.
(2006). Inflammation and cancer: How hot is the link? Biochemical
Pharmacology,72(11), 1605–1621.
Akimoto, M., Lizuka, M., Kanematsu, R., Yoshida, M., & Takenaga, K.
(2015). Anticancer effect of ginger extract against pancreatic cancer
cells mainly through reactive oxygen species‐mediated autotic cell
death. PLoS one,10(5), e0126605.
Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., & Hunt,
T. (2010). Biologia molecular da Célula. Artmed Editora: Courier
Corporation.
Ali, B. H., Blunden, G., Tanira, M. O., & Nemmar, A. (2008). Some phyto-
chemical, pharmacological and toxicological properties of ginger
(Zingiber officinale Roscoe): A review of recent research. Food and
Chemical Toxicology,46(2), 409–420.
Al‐Sadi, R., Guo, S., Ye, D., Dokladny, K., Alhmoud, T., Ereifej, L., …Ma, T. Y.
(2013). Mechanism of IL‐1βmodulation of intestinal epithelial barrier
involves p38 kinase and activating transcription factor‐2 activation.
The Journal of Immunology,190(12), 6596–6606.
Al‐Suhaimi, E. A., Al‐Riziza, N. A., & Al‐Essa, R. A. (2011). Physiological and
therapeutical roles of ginger and turmeric on endocrine functions. The
American Journal of Chinese Medicine,39(2), 215–231.
Ameer, F., Scandiuzzi, L., Hasnain, S., Kalbacher, H., & Zaidi, N. (2014). De
novo lipogenesis in health and disease. Metabolism,63(7), 895–902.
American Thoracic Society (2000). Idiopathic pulmonary fibrosis: Diagnosis
and treatment. International consensus statement. American Thoracic
Society (ATS), and the European Respiratory Society (ERS). American
Journal of Respiratory and Critical Care Medicine,161(2), 646–664.
Araki, Y., Katoh, T., Ogawa, A., Bamba, S., Andoh, A., Koyama, S., …Bamba,
T. (2005). Bile acid modulates transepithelial permeability via the gen-
eration of reactive oxygen species in the Caco‐2 cell line. Free Radical
Biology and Medicine,39(6), 769–780.
Araújo, A. P. S., & Galvão, D. C. A. (2010). Câncer ósseo: Enfoque sobre a
biologia do câncer. Revista Saúde e Pesquisa,3(3), 359–363.
Asif, M., Yehya, A. H. S., Al‐Mansoub, M. A., Revadigar, V., Ezzat, M. O.,
Khadeer Ahamed, M. B., …Abdul Majid, A. M. S. (2016). Anticancer
attributes of Illicium verum essential oils against colon cancer. South
African Journal of Botany,103, 156–161.
Badria, F. A. (1994). Is man helpless against cancer? An environmental
approach: Antimutagenic agents from Egyptian food and medicinal
preparations. Cancer Letters,84(1), 1–5.
Bak, M. J., Ok, S., Jun, M., & Jeong, W. S. (2012). 6‐shogaol rich extract
from ginger up regulates the antioxidant defense systems in cells and
Mice. Molecules,17(7), 8037–8055.
Balkwill, F. (2002). Tumor necrosis factor or tumor promoting factor?
Cytokine & Growth Factor Reviews,13(2), 135–141.
Barreiros, A. L., David, J. M., & David, J. P. (2006). Estresse oxidativo:
Relação entre geração de espécies reativas e defesa do organismo.
Química Nova,29(1), 113–123.
Benzie, I. F. F., & Wachtel‐Galor, S. (2011). The amazing and mighty ginger.
In Herbal medicine: Biomolecular and clinical aspects (2nd ed.). Boca
Raton (FL): CRC Press. cap. 7
Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014). Oxi-
dative stress: An essential factor in the pathogenesis of gastrointestinal
mucosal diseases. Physiological Reviews,94(2), 329–354.
Block, K. I., Gyllenhaal, C., Lwe, L., Amedei, A., Ruhul Amin, A. R. M., Amin,
A., …Zollo, M. A. (2015). Broad‐spectrum integrative design for cancer
prevention and therapy. Seminars in Cancer Biology,35, 276–304.
Bode, A. M., & Dong, Z. (2011). The amazing and mighty ginger. In Herbal
medicine: Biomolecular and clinical aspects (pp. 131–156). New York:
CRC Press, Taylor & Francis.
Bølling, A. K., Samuelsen, J. T., Morisbak, E., Ansteinsson, V., Becher, R.,
Dahl, J. E., & Mathisen, G. H. (2013). Dental monomers inhibit LPS‐
18 DE LIMA ET AL.

induced cytokine release from the macrophage cell line RAW264.7.
Toxicology Letters Journal,216(2–3), 130–138.
Bonaccio, M., Di Castelnuovo, A., De Curtis, A., Costanzo, S., Persichillo,
M., Donati, M. B., …De Gaetano, G. (2014). Adherence to the Mediter-
ranean diet is associated with lower platelet and leukocyte counts:
Results from the Moli‐sani study. Moli‐Sani Project Investigators,
123(9), 3037–3044.
Bryant, J., Picot, J., Levitt, G., Sullivan, I., Baxter, L., & Clegg, A. (2007).
Cardioprotection against the toxic effects of anthracyclines given to
children with cancer: A systematic review. Health Technology Assess-
ment,11(27), 1–84.
Butt, M. S., & Sultan, M. T. (2011). Ginger and its health claims: Molecular
aspects. Critical Reviews in Food Science and Nutrition,51(5), 383–393.
Chakraborty, D., Bishayee, K., Ghosh, S., Biswas, R., Mandal, S. K., &
Khuda‐Bukhsh, A. R. (2012). [6]‐Gingerol induces caspase 3 dependent
apoptosis and autophagy in cancer cells: Drug–DNA interaction and
expression of certain signal genes in HeLa cells. European Journal of
Pharmacology,694(1), 20–29.
Chang, K., & Kuo, C. (2015). 6‐Gingerol modulates proinflammatory
responses in dextran sodium sulfate (DSS)‐treated Caco‐2 cells and
experimental colitis in mice through adenosine monophosphate‐acti-
vated protein kinase (AMPK) activation. Food & Function,6,
3334–3341.
Chen, X., Wang, S., Wu, N., & Yang, C. S. (2004). Leukotriene A4 hydrolase
as a target for cancer prevention and therapy. Current Cancer Drug Tar-
gets,4(3), 267–283.
Choi, Y. Y., Kim, M. H., Hong J., Kim S.‐H., Yang, W. M. (2013). Dried ginger
(Zingiber officinalis) inhibits inflammation in a lipopolysaccharide‐
induced mouse model. Evidence‐Based Complementary and Alternative
Medicine, 914563, 9.
Clarkson, P. M., & Thompson, H. S. (2000). Antioxidants: What role do they
play in physical activity and health? The American Journal of Clinical
Nutrition,72(2), 637–646.
Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009).
Cancer‐related inflammation, the seventh hallmark of cancer: Links to
genetic instability. Carcinogenesis,30(7), 1073–1081.
Coulthard, L. R., White, D. E., Jones, D. L., Mcdermott, M. F., & Burchill, S.
A. (2009). P38 Mapk: Stress responses from molecular mechanisms to
therapeutics. Trends in Molecular Medicine,15(8), 369–379.
Coussens, L. M., Zitvogel, L., & Palucka, A. K. (2013). Neutralizing tumor‐
promoting chronic inflammation: A magic bullet? Science,339(6117),
286–291.
Coutinho, M. A., Muzitano, M. F., & Costa, S. S. (2009). Flavonoides:
Potenciais agentes terapêuticos para o processo inflamatório. Revista
Virtual de Química,1(3), 241–256.
Cragg, G. M., & Newman, D. J. (2013). Natural products: A continuing
source of novel drug leads. Biochimica et Biophysica Acta (BBA) ‐General
Subjects,1830(6), 3670–3695.
Cunningham, K. E., & Turner, J. R. (2012). Myosin light chain kinase: Pulling
the strings of epithelial tight junction function. Annals of the New York
Academy of Sciences,1258(1), 34–42.
Danciu, C., Vlaia, L., Fetea, F., Hancianu, M., Coricovac, D. E., Ciurlea, S. A.,
…Trandafirescu, C. (2015). Evaluation of phenolic profile, antioxidant
and anticancer potential of two main representants of Zingiberaceae
family against B164A5 murine melanoma cells. Biological Research,
48(1). https://doi.org/10.1186/0717‐6287‐48‐1
Danwilai, K., Konmun, J., Sripanidkulchai, B., & Subongkot, S. (2017).
Antioxidant activity of ginger extract as a daily supplement in cancer
patients receiving adjuvant chemotherapy: A pilot study. Cancer
Management and Research,9,11–18.
Demaria, S., Pikarsky, E., Karin, M., Coussens, L. M., Chen, Y. C., & El‐Omar,
E. M. (2010). Cancer and inflammation: Promise for biological therapy.
Journal of Immunotherapy,33(4), 335–351.
Dias, C. A. R., Moura, P. M. S. S., & D'Angeliz, C. E. M. (2011). A complexa
interação entre radicais livres, suplementação e doenças. Revista
Multidisciplinar das FIPMoc,10,34–43.
Dongare, S., Gupta, S. K., Mathur, R., Saxena, R., Mathur, S., Agarwal, R., …
Kumar, P. (2016). Zingiber officinale attenuates retinal microvascular
changes in diabetic rats via anti‐inflammatory and antiangiogenic
mechanisms. Molecular Vision,22, 599–609.
Droge, W. (2002). Free radicals in the physiological control of cell function.
Physiological Reviews,82(1), 47–95.
Duan, X., Li, J., Li, W., Xing, X., Zhang, Y., Zhao, L., …Li, B. (2016). Antiox-
idant tert‐butylhydroquinone ameliorates arsenic‐induced intracellular
damages and apoptosis through induction of Nrf2‐dependent antioxi-
dant responses as well as stabilization of anti‐apoptotic factor Bcl‐2
in human keratinocytes. Free Radical Biology and Medicine,94,74–87.
Eggler, A. L., Gay, K. A., & Mesecar, A. D. (2008). Molecular mechanisms of
natural products in chemoprevention: Induction of cytoprotective
enzymes by Nrf2. Molecular Nutrition & Food Research,52, S84–S94.
Ekowati, H., Achmad, A., Prasasti, E., Wasito, H., Sri, K., Hidayati, Z., &
Ekasari, T. (2012). Zingiber officinale,Piper retrofractum and combination
induced apoptosis and p53 expression in myeloma and WiDr cell lines.
HAYATI Journal of Biosciences,19(3), 137–140.
Elkady, A. I., Abuzinadah, O. A., Baeshen, N. A., Rahmy, T. R. (2012). Differ-
ential control of growth, apoptotic activity, and gene expression in
human breast cancer cells by extracts derived from medicinal herbs
Zingiber officinale.Journal of Biomedicine and Biotechnology, 2012,
614356, 1–14.
Elkady, A. I., Hussein, R. A. E. H., & Abu‐Zinadah, O. A. (2014a). Differential
control of growth, apoptotic activity and gene expression in human
colon cancer cells by extracts derived from medicinal herbs, Rhazya
stricta and Zingiber officinale and their combination. World Journal of
Gastroenterology,20(41), 15275–15288.
Elkady, A. I., Hussein, R. A. E. H., Abu‐Zinadah, O. A. (2014b). Effects of
crude extracts from medicinal herbs Rhazya stricta and Zingiber
officinale on growth and proliferation of human brain cancer cell line
in vitro. BioMed Research International,2014, 260210, 1–16.
El‐Naggar, M. H., Mira, A., Bar, F. M. A., Shimizu, K., Amer, M. M., & Badria,
F. A. (2017). Synthesis, docking, cytotoxicity, and LTA 4 H inhibitory
activity of new gingerol derivatives as potential colorectal cancer ther-
apy. Bioorganic & Medicinal Chemistry,25(3), 1277–1285.
Escarcega, R. O., Fuentes‐Alexandro, S., Garcia‐Carrasco, M., Gatica, A., &
Zamora, A. (2007). The transcription factor nuclear factor‐kappa B
and cancer. Clinical Oncology,19(2), 154–161.
Fan, J. Z., Yang, X., & Bi, Z. G. (2015). The effects of 6‐gingerol on prolifer-
ation, differentiation, and maturation of osteoblast‐like MG‐63 cells.
Brazilian Journal of Medical and Biological Research,48(7), 637–643.
Ferreira, L. M. (2010). Cancer metabolism: The Warburg effect today.
Experimental and Molecular Pathology,89(3), 372–380.
Ferrucci, L. M., Daniel, C. R., Kapur, K., Chadha, P., Shetty, H., Graubard, B.
I., & Chatterjee, N. (2010). Measurement of spices and seasonings in
India: Opportunities for cancer epidemiology and prevention. Asian
Pacific Journal of Cancer Prevention,11(6), 1621–1629.
Figarola, J. L., Singhal, P., Rahbar, S., Gugiu, B. G., Awasthi, S., & Singhal, S.
S. (2013). COH‐SR4 reduces body weight, improves glycemic control
and prevents hepatic steatosis in high fat diet‐induced obese mice.
PLoS One,8(12), e83801.
Flohe, L. (2010). Changing paradigms in thiology: From antioxidant defense
toward redox regulation. Methods in Enzymology,473,1–39.
Franceschi, C. (2007). Inflammaging as a major characteristic of old people:
Can it be prevented or cured? Nutrition Reviews,65, S173–S176.
Franceschi, C., Bonafè, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani,
E., & De Benedictis, G. (2000). Inflamm‐aging: An evolutionary perspec-
tive on immunosenescence. Annals of the New York Academy of
Sciences,908(1), 244–254.
Freire, O. M., & Van Dyke, E. T. (2014). Natural resolution of inflammation.
Periodontology 2000,63(1), 149–164.
DE LIMA ET AL.19

Gajewski, T. F., Schreiber, H., & Fu, Y. X. (2013). Innate and adaptive
immune cells in the tumor microenvironment. Nature Immunology,
14(10), 1014–1022.
Ghasemzadeh, A., Jaafar, H. Z. E., & Rahmat, A. (2015). Optimization proto-
col for the extraction of 6‐gingerol and 6‐shogaol from Zingiber
officinale var. rubrum Theilade and improving antioxidant and antican-
cer activity using response surface methodology. BMC Complementary
and Alternative Medicine,15, 258–265.
Giustarini, D., Dalle‐Donne, I., Tsikas, D., & Rossi, R. (2009).
Oxidative stress and human diseases: Origin, link, measurement,
mechanisms, and biomarkers. Critical Reviews in Clinical Laboratory Sci-
ences,46(5–6), 241–281.
Gupta, S. C., Hevia, D., Patchva, S., Park, B., Koh, W., & Aggarwal, B. B.
(2012). Upsides and downsides of reactive oxygen species for cancer:
The roles of reactive oxygen species in tumorigenesis, prevention,
and therapy. Antioxidants & Redox Signaling,16(11), 1295–1322.
Habib, S. H. M., Makpol, S., Hamid, N. A. A., Das, S., Ngah, W. Z. W., &
Yusof, Y. A. M. (2008). Ginger extract (Zingiber officinale) has anti‐can-
cer and anti‐inflammatory effects on ethionine‐induced hepatoma
rats. Clinics,63(6), 807–813.
Hamanaka, R. B., & Chandel, N. S. (2010). Mitochondrial reactive oxygen
species regulate cellular signaling and dictate biological outcomes.
Trends in Biochemical Sciences,35(9), 505–513.
Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell,
100(1), 57–70.
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next gen-
eration. Cell,144(5), 646–674.
Hercos, T. M., Vieira, F. S., Oliveira, M. S., Buetto, L. S., Shimura, C. M. N., &
Sonobe, H. M. N. (2014). O trabalho dos profissionais de enfermagem
em unidades de terapia intensiva na assistência ao paciente oncológico.
Revista Brasileira de Cancerologia,60(1), 51–58.
Hopperton, K. E., Duncan, R. E., Bazinet, R. P., & Archer, M. C. (2014). Fatty
acid synthase plays a role in cancer metabolism beyond providing fatty
acids for phospholipid synthesis or sustaining elevations in glycolytic
activity. Experimental Cell Research,320(2), 302–310.
Horner, S. M., Defilippis, R. A., Manuelidis, L., & Dimaio, D. (2004). Repres-
sion of the human papillomavirus E6 gene initiates p53‐dependent,
telomerase‐independent senescence and apoptosis in HeLa cervical
carcinoma cells. Journal of Virology,78(8), 4063–4073.
Hosseini, A., Shafiee‐Nick, R., & Mousavi, S. H. (2014). Combination of
Nigella sativa with Glycyrrhiza glabra and Zingiber officinale augments
their protective effects on doxorubicin‐induced toxicity in h9c2 cells.
Iranian Journal of Basic Medical Sciences,17(12), 993–1000.
Houssen, M. E., Ragab, A., Mesbah, A., El‐Samanoudy, A. Z., Othman, G.,
Moustafa, A. F., & Badria, F. A. (2010). Natural anti‐inflammatory prod-
ucts and leukotriene inhibitors as complementary therapy for bronchial
asthma. Clinical Biochemistry,43(10), 887–890.
Howells, R. E. J., Dhar, K. K., Hoban, P. R., Jones, P. W., Fryer, A. A.,
Redman, C. W. E., & Strange, R. C. (2004). Association between gluta-
thione‐S‐transferase GSTP1 genotypes, GSTP1 over‐expression, and
outcome in epithelial ovarian cancer. International Journal of Gynecolog-
ical Cancer,14(2), 242–250.
Huang, J., Wang, Y., Xie, Z., Zhou, Y., Zhang, Y., & Wan, X. (2014). The anti‐
obesity effects of green tea in human intervention and basic molecular
studies. European Journal of Clinical Nutrition,68(10), 1075–1087.
Impheng, H., Richert, L., Pekthong, D., Scholfield, C. N., Pongcharoen, S.,
Pungpetchara, I., & Srisawang, P. (2015). [6]‐Gingerol inhibits de novo
fatty acid synthesis and carnitine palmitoyltransferase‐1 activity which
triggers apoptosis in HepG2. American Journal of Cancer Research,5(4),
1319–1336.
INCA. INCA. Instituto Nacional de Câncer José Alencar Gomes da Silva
(INCA). Incidência de Câncer no Brasil ‐Estimativa 2014. Disponível
em: <http://www.inca.gov.br/estimativa/2014/index. asp? ID=2>.
Data de acesso: 13/10/2017.
INCA. INCA. Instituto Nacional de Câncer José Alencar Gomes da Silva
(INCA). Incidência de Câncer no Brasil‐Estimativa 2016. Disponível
em: <http://www.inca.gov.br/estimativa/2016/index. asp? ID=2>.
Data de acesso: 13/10/2017.
Jacobs, A. T., & Ignarro, L. J. (2001). Lipopolysaccharide‐induced expres-
sion of interferon‐βmediates the timing of inducible nitric‐oxide
synthase induction in RAW 264.7 macrophages. Journal of Biological
Chemistry,276(51), 47950–47957.
Jayakumar, T., Thomas, P. A., & Geraldine, P. (2009). In‐vitro antioxidant
activities of an ethanolic extract of the oyster mushroom, Pleurotus
ostreatus.Innovative Food Science & Emerging Technologies,10(2),
228–234.
Jeong, C. H., Bode, A. M., Pugliese, A., Cho, Y. Y., Kim, H. G., Shim, J. H., &
Dong, Z. (2009). [6]‐Gingerol suppresses colon cancer growth by
targeting leukotriene A4 hydrolase. Cancer Research,69(13),
5584–5591.
Jiang, H. (2005). Hongliang. Modern tools to study traditional medicinal
plants: Ginger and turmeric. PhD Thesis, The University of Arizona,
Tucson.
Jiang, Y., Turgeon, D. K., Wright, B. D., Sidahmed, E., Ruffin, M. T., Brenner,
D. E., & Zick, S. M. (2013). Effect of ginger root on cyclooxygenase‐1
and 15‐hydroxyprostaglandin dehydrogenase expression in colonic
mucosa of humans at normal and increased risk of colorectal cancer.
European Journal of Cancer Prevention,22(5), 455–460.
Ju, S. A., Park, S. M., Lee, Y. S., Bae, J. H., Yu, R., Suh, J., & Kim, B. S. (2012).
Administration of 6‐gingerol greatly enhances the number of tumor‐
infiltrating lymphocytes in murine tumors. International Journal of Can-
cer,130, 2618–2628.
Kaefer, C. M., & Milner, J. A. (2008). The role of herbs and spices in cancer
prevention. The Journal of Nutritional Biochemistry,19(6), 347–361.
Kang, O. H., Kim, S. B., Seo, Y. S., Joung, D. K., Mun, S. H., Choi, J. G., &
Kwon, D. Y. (2013). Curcumin decreases oleic acid‐induced lipid accu-
mulation via AMPK phosphorylation in hepatocarcinoma cells.
European Review for Medical and Pharmacological Sciences,17(19),
2578–2586.
Karna, P., Chagani, S., Gundala, S. R., Rida, P. C., Asif, G., Sharma, V., &
Aneja, R. (2012). Benefits of whole ginger extract in prostate cancer.
British Journal of Nutrition,107(4), 473–484.
Kaspar, J. W., Niture, S. K., & Jaiswal, A. K. (2009). Nrf2: INrf2 (Keap1) sig-
naling in oxidative stress. Free Radical Biology and Medicine,47(9),
1304–1309.
Kaur, I. P., Deol, P. K., Kondepudi, K. K., & Bishnoi, M. (2016). Anticancer
potential of ginger: Mechanistic and pharmaceutical aspects. Current
Pharmaceutical Design,22(27), 4160–4172.
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival
responses to environmental stresses via the Keap1‐Nrf2‐ARE pathway.
Annual Review of Pharmacolology and Toxicology,47,89–116.
Khaki, A., & Fathiazad, F. (2012). Diabetic nephropathy—Using herbals in
diabetic nephropathy prevention and treatment—The role of ginger
(Zingiber officinale) and onion (Allium cepa) in diabetics' nephropathy.
In A compendium of essays on alternative therapy. InTech, Rijeka,
Croatia.
Khatami, M. (2009). Inflammation, aging, and cancer: Tumoricidal versus
tumorigenesis of immunity. Cell Biochemistry and Biophysics,55(2),
55–79.
Kim, S. O., Chun, K. S., Kundu, J., & Surh, Y. J. (2004). Inhibitory effects of
[6]‐gingerol on PMA‐induced COX‐2 expression and activation of
NF‐κB and p38 MAPK in mouse skin. BioFactors,21(1–4), 27–31.
Kim, S. O., Kim, M. R. (2013). [6]‐gingerol prevents disassembly of cell junc-
tions and activities of MMPs in invasive human pancreas cancer cells
through ERK/NF‐κB/snail signal transduction pathway. Evidence‐Based
Complementary and Alternative Medicine,2013, 761852, 1–9.
Kinghorn, A. D., Pan, L., Fletcher, J. N., & Chai, H. (2011). The relevance of
higher plants in lead compound discovery programs. Journal of Natural
Products,74(6), 1539–1555.
Koury, J. C., & Donangelo, C. M. (2003). Zinco, estresse oxidativo e
atividade física. Revista de Nutrição,16(4), 433–441.
20 DE LIMA ET AL.

Krystona, T. B., Georgieva, A. B., Pissis, P., & Georgakilas, A. G. (2011). Role
of oxidative stress and DNA damage in human carcinogenesis. Muta-
tion Research, Fundamental and Molecular Mechanisms of Mutagenesis,
711(1), 193–201.
Kubra, I. R., & Rao, L. J. (2012). An impression on current developments in
the technology, chemistry, and biological activities of ginger (Zingiber
officinale Roscoe). Critical Reviewes in Food Science and Nutrition,
52(8), 651–688.
Kubra, I. R., & Rao, L. J. M. (2012a). Microwave drying of ginger (Zingiber
officinale Roscoe) and its effects on polyphenolic content and antioxi-
dant activity. International Journal of Food Science and Technology,47,
2311–2317.
Kundu, J. K., & Surh, Y. J. (2008). Inflammation: Gearing the journey to can-
cer. Mutation Research, Reviews in Mutation Research,659(1), 15–30.
Kundu, J. K., & Surh, Y. J. (2012). Emerging avenues linking inflammation
and cancer. Free Radical Biology and Medicine,52(9), 2013–2037.
Lachumy, S. J., Oon, C. E., Deivanai, S., Saravanan, D., Vijayarathna, S.,
Choong, Y. S., & Sasidharan, S. (2013). Herbal remedies for combating
irradiation: A green anti‐irradiation approach. Asian Pacific Journal of
Cancer Prevention,14(10), 5553–5565.
Lee, C., Park, G. H., Kim, C. Y., & Jang, J. H. (2011). [6]‐Gingerol attenuates
β‐amyloid‐induced oxidative cell death via fortifying cellular antioxi-
dant defense system. Food and Chemical Toxicology,49(6), 1261–1269.
Lee, C. H., Park, S. W., Kim, Y. S., Kang, S. S., Kim, J. A., Lee, S. H., & Lee, S.
M. (2007). Protective mechanism of glycyrrhizin on acute liver injury
induced by carbon tetrachloride in mice. Biological and Pharmaceutical
Bulletin,30(10), 1898–1904.
Lee, D.‐H., Kimb, D.‐W., Jungc, C.‐H., Leea, Y. J., & Parkd, D. (2014).
Gingerol sensitizes TRAIL‐induced apoptotic cell death of glioblastoma
cells. Toxicology and Applied Pharmacology,279(3), 253–265.
Lee, H. S., Seo, E. Y., & Kim, W. K. (2008). [6]‐Gingerol inhibits metastasis
of MDA‐MB‐231 human breast cancer cells. The Journal of Nutritional
Biochemistry,19(5), 313–319.
Lee, J. S., & Surh, Y. J. (2005). Nrf2 as a novel molecular target for chemo-
prevention. Cancer Letters,224(2), 171–184.
Lee, S. E., Yang, H., Son, G. W., Park, H. R., Park, C. S., Jin, Y. H., & Park, Y.
S. (2015). Eriodictyol protects endothelial cells against oxidative stress‐
induced cell death through modulating ERK/Nrf2/ARE‐dependent
heme oxygenase‐1 expression. International Journal of Molecular
Sciences,16(7), 14526–14539.
Li, H. X., Mcgrath, K. C. Y., Van, H., Tran, V. H., Li, Y. M., Duke, C. C., &
Heather, A. K. (2013). Attenuation of proinflammatory responses by
S‐[6]‐Gingerol via inhibition of ROS/NF‐Kappa B/COX2 activation in
HuH7 cells. Evidence‐Based Complementary and Alternative Medicine,
2013, 146142, 1–8.
Li, Y., Xu, B., Xu, M., Chen, D., Xiong, Y., Lian, M., …Lin, Y. (2017). 6‐
Gingerol protects intestinal barrier from ischemia/reperfusion‐induced
damage via inhibition of p38 MAPK to NF‐κB signalling. Pharmacologi-
cal Research,119, 137–148.
Lin, A., & Karin, M. (2003). NF‐κB in cancer: A marked target. Seminars in
Cancer Biology,13(2), 107–114.
Lin, C. B., Lin, C. C., & Tsay, G. J. (2012). 6‐Gingerol inhibits growth of
colon cancer cell LoVo via induction of G2/M arrest. Evidence‐Based
Complementary and Alternative Medicine,Article ID 326096,1–7.
Lin, W. W., & Karin, M. (2007). A cytokine‐mediated link between innate
immunity, inflammation, and cancer. Journal of Clinical Investigation,
117(5), 1175.
Lin, Y., Liu, X., Cheng, Y., Yang, J., Huo, Y., & Zhang, C. (2009). Involvement
of microRNAs in hydrogen peroxide‐mediated gene regulation and cel-
lular injury response in vascular smooth muscle cells. Journal of
Biological Chemistry,284(12), 7903–7913.
Liou, G. Y., & Storz, P. (2010). Reactive oxygen species in cancer. Free
Radical Research,44(5), 479–496.
Liu, C., Kao, C.‐L., Tseng, Y.‐T., Lo, Y. C., & Chen, C.‐Y. (2017). Ginger phy-
tochemicals inhibit cell growth and modulate drug resistance factors in
docetaxel resistant prostate cancer cell. Molecules,22, 1477.
Luo, J., Solimini, N. L., Elledge, S. J., & Stephen, J. (2009). Principles of can-
cer therapy: Oncogene and non‐oncogene addiction. Cell,136(5),
823–837.
Machado, H., Nagem, T. J., Peters, V. M., Fonseca, C. S., & Oliveira, T. T.
(2010). Flavonóides e seu potencial terapêutico. Boletim Do Centro de
Biologia da Reprodução,27(1/2), 33–39.
Manasa, D., Srinivas, P., & Sowbhagya, H. B. (2013). Enzyme‐assisted
extraction of bioactive compounds from ginger (Zingiber officinale
Roscoe). Food Chemistry,139(1), 509–514.
Manju, V., & Nalini, N. (2005). Chemopreventive efficacy of ginger, a natu-
rally occurring anticarcinogen during the initiation, post‐initiation
stages of 1,2 dimethylhydrazine‐induced colon cancer. Clinica Chimica
Acta,358(1), 60–67.
Mantovani, A. (2005). Cancer: Inflammation by remote control. Nature,
435(7043), 752–753.
Mantovani, A. (2009). Cancer: Inflaming metastasis. Nature,457(7225),
36–37.
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer‐related
inflammation. Nature,454(7203), 436–444.
Martin, K. R. (2006). Targeting apoptosis with dietary bioactive agents.
Experimental Biology and Medicine,231, 117–129.
McLaughlin, S. P. (2005). Ginger: The genus Zingiber. In P. N. Ravindran, &
K. Nirmal Babu (Eds.), Medicinal and aromatic plants‐industrial profiles.
Boca Raton: CRC Press. ISBN: 0‐415‐32468‐8.
Medzhitov, R. (2010). Inflammation 2010: New adventures of an old flame.
Cell,140(6), 771–776.
Melo, S., Yugar‐Todelo, J. C., Coca, A. P., & Júnior, H. M. (2007).
Hipertensão arterial, aterosclerose e inflamação: o endotélio como
órgão‐alvo. Revista Brasileira Hipertens,14(4), 234–238.
Mestre, J. R., Mackrell, P. J., Rivadeneira, D. E., Stapleton, P. P., Tanabe, T.,
& Daly, J. M. (2001). Redundancy in the signaling pathways and pro-
moter elements regulating cyclooxygenase‐2 gene expression in
endotoxin‐treated macrophage/monocytic cells. Journal of Biological
Chemistry,276(6), 3977–3982.
Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani,
H., …Motohashi, H. (2012). Nrf2 redirects glucose and glutamine into
anabolic pathways in metabolic reprogramming. Cancer Cell,22(1),
66–79.
Motawi, T. K., Hamed, M. A., Shabana, M. H., Hashem, R. M., & Naser, A. F.
(2011). Zingiber officinale acts as a nutraceutical agent against liver
fibrosis. Nutrition and Metabolism,8(40), 1–11.
Newman, D. J., & Cragg, G. M. (2012). Natural products as sources of new
drugs over the 30 years from 1981 to 2010. Journal of Natural Products,
75(3), 311–335.
Niture, S. K., & Jaiswal, A. K. (2012). Nrf2 protein up‐regulates
antiapoptotic protein Bcl‐2 and prevents cellular apoptosis. Journal of
Biological Chemistry,287(13), 9873–9886.
Nogueira, V., & Hay, N. (2013). Molecular pathways: Reactive oxygen spe-
cies homeostasis in cancer cells and implications for cancer therapy.
Clinical Cancer Research,19(16), 4309–4314.
Ohnishi, S., Ma, N., Thanan, R., Pinlaor, S., Hammam, O., Murata, M. (2013).
DNA damage in inflammation‐related carcinogenesis and cancer stem
cells. Oxidative Medicine and Cellular Longevity,2013, 387014, 1–9.
Omoni, A., & Aluko, R. (2005). The anti‐carcinogenic and anti‐atherogenic
effects of lycopene: A review. Trends in Food Science & Technology,
16(8), 344–350.
Oyagbemi, A. A., Saba, A. B., & Azeez, O. I. (2010). Molecular targets of [6]‐
gingerol: Its potential roles in cancer chemoprevention. BioFactors,
36(3), 169–178.
Papas, A. M. (1999). Diet and antioxidant status. Food and Chemical Toxicol-
ogy,37(9–10), 999–1007.
DE LIMA ET AL.21

Parvizzadeh, N., Sadeghi, S., Irani, S., Iravani, A., Kalayee, Z., Rahimi, N. A.,
Zamani, Z. (2014). A metabonomic study of the effect of methanol
extract of ginger on Raji cells using 1HNMR spectroscopy. Biotechnol-
ogy Research International,2014, 572534, 1–8.
Pereira‐Filho, G., Ferreira, C., Schwengber, A., Marroni, C., Zettler, C., &
Marroni, N. (2008). Role of N‐acetylcysteine on fibrosis and oxidative
stress in cirrhotic rats. Arquivos de Gastroenterologia,45(2), 156–162.
Philip, M., Rowley, D. A., & Schreiber, H. (2004). Inflammation as a tumor
promoter in cancer induction. Seminars in Cancer Biology. Academic
Press, 14(6), 433–439.
Prasad, S., Tyagi, A.K. (2015). Ginger and its constituents: Role in preven-
tion and treatment of gastrointestinal cancer. Gastroenterology
Research and Practice,2015, 142979, 1–11.
Qi, F., Zhao, L., Zhou, A., Zhang, B., Li, A., Wang, Z., & Han, J. (2015). The
advantages of using traditional Chinese medicine as an adjunctive ther-
apy in the whole course of cancer treatment instead of only terminal
stage of cancer. Bioscience Trends,9,16–34.
Radhakrishnan, E., Bava, S. V., Narayanan, S. S., Nath, L. R., Thulasidasan, A.
K. T., & Soniya, E. V. (2014). [6]‐Gingerol induces caspase‐dependent
apoptosis and prevents PMA‐induced proliferation in colon cancer cells
by inhibiting MAPK/AP‐1 signaling. PLoS one,9(8), e104401.
Rastogi, N., Duggal, S., Singh, S. K., Porwal, K., Srivastava, V. K., Maurya, R.,
…Mishra, D. P. (2015). Proteasome inhibition mediates p53 reactiva-
tion and anti‐cancer activity of 6‐gingerol in cervical cancer cells.
Oncotarget,6(41), 43310–43325.
Rastogi, N., Gara, R. K., Trivedi, R., Singh, A., Dixit, P., Maurya, R., & Mishra,
D. P. (2014). (6)‐Gingerolinduced myeloid leukemia cell death is initi-
ated by reactive oxygen species and activation of miR‐27b
expression. Free Radical Biology and Medicine,68, 288–301.
Rauf, A., Imran, M., Butt, M. S., Nadeem, M., Peters, D. G., & Mubarak, M.
S. (2018). Resveratrol as an anti‐cancer agent: A review. Critical Reviews
in Food Science and Nutrition,58, 1428–1447.
Reader, J., Holt, D., & Fulton, A. (2011). Prostaglandin E2 EP receptors as
therapeutic targets in breast cancer. Cancer and Metastasis Reviews,
30(3–4), 449–463.
Rodriguez‐Enriquez, S., Marin‐Hernandez, A., Gallardo‐Perez, J. C., &
Moreno‐Sanchez, R. (2009). Kinetics of transport and phosphorylation
of glucose in cancer cells. Journal of Cellular Physiology,221(3),
552–559.
Ruana, D., & So, S. P. (2014). Prostaglandin E 2 produced by inducible
COX‐2 and mPGES‐1 promoting cancer cell proliferation in vitro and
in vivo. Life Sciences,116(1), 43–50.
Salim, A. A., Chin, Y. W., & Kinghorn, A. D. (2008). Drug discovery from
plants. Bioactive Molecules and Medicinal Plants,1–24. Springer
Schadich, E., Hlaváč, J., Volná, T., Varanasi, L., Hajdúch, M., Džubák, P.
(2016). Effects of ginger phenylpropanoids and quercetin on Nrf2‐
ARE pathway in human BJ fibroblasts and HaCaT keratinocytes.
BioMed Research International,2016, 2173275, 1–6.
Sedger, L. M., & Mcdermott, M. F. (2014). TNF and TNF‐receptors: From
mediators of cell death and inflammation to therapeutic giants—Past,
present and future. Cytokine & Growth Factor Reviews,25(4), 453–472.
Semwal, R. B., Semwal, D. K., Combrinck, S., & Viljoen, A. M. (2015).
Gingerols and shogaols: Important nutraceutical principles from ginger.
Phytochemistry,117, 554–568.
Serhan, C. N. (2014). Pro‐resolving lipid mediators are leads for resolution
physiology. Nature,510(7503), 92–101.
Serhan, C. N., & Petasis, N. A. (2011). Resolvins and protectins in inflamma-
tion resolution. Chemical Reviews,111(10), 5922–5943.
Seyed, M. A., Jantan, I., Bukhari, S. N. A., & Vijayaraghavan, K. (2016). A
comprehensive review on the chemotherapeutic potential of
piceatannol for cancer treatment, with mechanistic insights. Journal of
Agricultural and Food Chemistry,64, 725–737.
Sharif, T., Alhosin, M., Auger, C., Minker, C., Kim, J. H., Etienne‐Selloum, N.,
…Schini‐Kerth, V. B. (2012). Aronia melanocarpa juice induces a
redox‐sensitive p73‐related caspase 3‐dependent apoptosis in human
leukemia cells. PLoS one,7(3), e32526.
Shukla, Y., & Singh, M. (2007). Cancer preventive properties of ginger: A
brief review. Food and Chemical Toxicology,45(5), 683–690.
Simone, N. L., Soule, B. P., Ly, D., Saleh, A. D., Savage, J. E., Degraff, W., …
Mitchell, J. B. (2009). Ionizing radiation‐induced oxidative stress alters
miRNA expression. PLoS one,4(7), e6377.
Sousa, C. M. M., Silva, H. R., Vieira‐Junior, G. M., Ayres, M. C. C., Costa, C.
L. C., & Araújo, D. S. (2007). Fenóis totais e atividade antioxidante de
cinco plantas medicinais. Química Nova,30(2), 351–355.
Souza, W. F., Araujo, W. M., Junior, J. C. M., & Morgado, J. A. (2014).
Sinalização celular em câncer. Ciência e Cultura,66(1), 30–33.
Srinivasan, K. (2014). Antioxidant potential of spices and their active con-
stituents. Critical Reviews in Food Science and Nutrition,54(3), 352–372.
Su, L., Nalle, S. C., Shen, L., Turner, E. S., Singh, G., Breskin, L. A., …Turner,
J. R. (2013). TNFR2 activates MLCK‐dependent tight junction dysregu-
lation to cause apoptosis‐mediated barrier loss and experimental
colitis. Gastroenterology,145(2), 407–415.
Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K., & Finkel, T. (1995).
Requirement for generation of H
2
O
2
for platelet‐derived growth factor
signal transduction. Science,270(5234), 296–299.
Surh, Y. J. (2003). Cancer chemoprevention with dietary phytochemicals.
Nature Reviews Cancer,3(10), 768–780.
Tahir, A. A., Sani, N. F. A., Murad, N. A., Makpol, S., Ngah, W. Z. W., &
Yusof, Y. A. M. (2015). Combined ginger extract & Gelam honey mod-
ulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29
cells. Nutrition Journal,14(31), 1–10.
Tan, S., De Vries, G. E., Van Der Zee, A. G. J., & De Jong, S. (2012). Antican-
cer drugs aimed at E6 and E7 activity in HPV‐positive cervical cancer.
Current Cancer Drug Targets,12(2), 170–184.
Tidefelt, U., Elmhorn‐Rosenborg, A., Paul, C., Hao, X. Y., Mannervik, B., &
Eriksson, L. C. (1992). Expression of glutathione transferase pas a pre-
dictor for treatment results at different stages of acute
nonlymphoblastic leukemia. Cancer Research,52(12), 3281–3285.
Trachootham, D., Lu, W., Ogasawara, M. A., Valle, N. R., & Huang, P.
(2008). Redox regulation of cell survival. Antioxidants & Redox Signaling,
10(8), 1343–1374.
Tuntiwechapikul, W., Taka, T., Songsomboon, C., Kaewtunjai, N.,
Imsumran, A., & Makonkawkeyoon, L. (2010). Ginger extract inhibits
human telomerase reverse transcriptase and c‐Myc expression in
A549 lung cancer cells. Journal of Medicinal Food,13(6), 1347–1354.
Vemuri, S. K., Banala, R. R., Subbaiah, G. P. V., Srivastava, S. K., Reddy, A. V.
G., & Malarvili, T. (2017). Anti‐cancer potential of a mix of natural
extracts of turmeric, ginger and garlic: A cell‐based study. Egyptian
Joural of Basic and Applied Science,4, 332–344.
Vincent, J. L., Sun, Q., & Dubois, M. J. (2002). Clinical trials of immunomod-
ulatory therapies in severe sepsis and septic shock. Clinical Infectious
Diseases,34(8), 1084–1093.
Vipin, A. V., Raksha Rao, K., Kurrey, N. K., Anu Appaiah, K. A., &
Venkateswaran, G. (2017). Protective effects of phenolics rich extract
of ginger against aflatoxin B1‐induced oxidative stress and hepatotox-
icity. Biomedicine & Pharmacotherapy,91, 415–424.
Wang, B., Sun, J., Ma, Y., Wu, G., Tian, Y., Shi, Y., & Le, G. (2014). Resver-
atrol preserves mitochondrial function, stimulates mitochondrial
biogenesis, and attenuates oxidative stress in regulatory T cells of mice
fed a high‐fat diet. Journal of Food Science,79(9), 1823–1831.
Wang, S., Sun, X., Jiang, L., Liu, X., Chen, M., Yao, X., …Yang, G. (2016). 6‐
Gingerol induces autophagy to protect HUVECs survival from apopto-
sis. Chemico‐Biological Interactions,256, 249–256.
Wang, Z., Liu, Y., Han, N., Chen, X., Yu, W., Zhang, W., & Zou, F. (2010).
Profiles of oxidative stress‐related microRNA and mRNA expression
in auditory cells. Brain Research,1346,14–25.
Waris, G., & Ahsan, H. (2006). Reactive oxygen species: Role in the devel-
opment of cancer and various chronic conditions. Journal of
Carcinogenesis,5(14), 1–8.
22 DE LIMA ET AL.

Wehner, S., Straesser, S., Vilz, T. O., Pantelis, D., Sielecki, T., Cruz, V. F., …
Kalff, J. C. (2009). Inhibition of p38 mitogen‐activated protein kinase
pathway as prophylaxis of postoperative ileus in mice. Gastroenterol-
ogy,136(2), 619–629.
Wen, S. H., Ling, Y. H., Li, Y., Li, C., Liu, J. X., Li, Y. S., …Liu, K. X. (2013).
Ischemic postconditioning during reperfusion attenuates oxidative
stress and intestinal mucosal apoptosis induced by intestinal ische-
mia/reperfusion via aldose reductase. Surgery,153(4), 555–564.
Wong, Y. N., Rossignol, D., Rose, J. R., Kao, R., Carter, A., & Lynn, M.
(2003). Safety, pharmacokinetics, and pharmacodynamics of E5564, a
lipid A antagonist, during an ascending single‐dose clinical stud. Journal
of Clinical Pharmacology,43(7), 735–742.
Wu, S., Ko, Y. S., Teng, M. S., Ko, Y. L., Hsu, L. A., Hsueh, C., …Lee, Y. S.
(2002). Adriamycin‐induced cardiomyocyte and endothelial cell apo-
ptosis: In vitro and in vivo studies. Journal of Molecular and Cellular
Cardiology,34(12), 1595–1607.
Wyckoff, T. J. O., Raetz, C. R. H., & Jackman, J. E. (1998). Antibacterial and
anti‐inflammatory agents that target endotoxin. Trends in Microbiology,
6(4), 154–159.
Xia, B., Liu, H., Xie, J., Wu, R., & Li, Y. (2015). Akt enhances nerve growth
factor‐induced axon growth via activating the Nrf2/ARE pathway.
International Journal of Molecular Medicine,35(5), 1426–1432.
Yamamoto, Y., Konishi, H., Ichikawa, D., Arita, T., Shoda, K., Komatsu, S., …
Otsuji, E. (2013). Significance of GSTP1 for predicting the prognosis
and chemotherapeutic efficacy in esophageal squamous cell carcinoma.
Oncology Reports,30(4), 1687–1694.
Yang, Q., Li, W., She, H., Dou, J., Duong, D. M., Du, Y., …Mao, Z. (2015).
Stress induces p38 MAPK‐mediated phosphorylation and inhibition of
Drosha‐dependent cell survival. Molecular Cell,57(4), 721–734.
Yehya, A. H., Asif, M., Tan, Y. J., Sasidharan, S., Majid, A. M. A., & Oon, C. E.
(2017). Broad spectrum targeting of tumor vasculature by medicinal
plants: An updated review. Journal of Herbal Medicine,9,1
–13.
Yildrin, A., Mavi, A., & Kara, A. A. (2001). Determination of antioxidant and
antimicrobial activities of Rumexcrispus L. extracts. Journal of Agricul-
tural and Food Chemistry,49(8), 4083–4089.
Yong, H. Y., Koh, M. S., & Moon, A. (2009). The p38 MAPK inhibitors for
the treatment of inflammatory diseases and cancer. Expert Opinion on
Investigational Drugs,8(12), 1893–1905.
Yoon, S. O., Kim, M. M., & Chung, A. S. (2001). Inhibitory effect of selenite
on invasion of HT1080 tumor cells. The Journal of Biological Chemistry,
276(23), 20085–20092.
Young, H. Y., & Chen, G. L. (2002). Analytical and stability of ginger repa-
rations. Journal of Food and Drug Analysis,10, 149–153.
Yu, B. P. (1994). Cellular defenses against damage from reactive oxygen
species. Physiological Reviews,74, 139–163.
Yusof, Y. A. M., Ahmad, N. S., Sulaiman, S., & Murad, N. A. (2009). Chemo-
preventive efficacy of ginger (Zingiber officinale) in ethionine induced
rat hepatocarcinogenesis. African Journal of Traditional, Complementary,
and Alternative Medicines,6(1), 87–93.
Zaidi, N., Lupien, L., Kuemmerle, N. B., Kinlaw, W. B., Swinnen, J. V., &
Smans, K. (2013). Lipogenesis and lipolysis: The pathways exploited
by the câncer cells to acquire fatty acids. Progress in Lipid Research,
52(4), 585–589.
Zhang, F., Zhang, J. G., Qu, J., Zhang, Q., Prasad, C., & Wei, Z. J. F. (2017).
Assessment of anti‐cancerous potential of 6‐gingerol (Tongling White
Ginger) and its synergy with drugs on human cervical adenocarcinoma
cells. Food and Chemical Toxicology,109, 910–922.
Zhang, J., Shen, B., & Lin, A. (2007). Novel strategies for inhibition of the
P38 Mapk pathway. Trends in Pharmacological Sciences,28(6),
286–295.
Zhang, Q., Zhu, B., & Li, Y. (2017). Resolution of cancer‐promoting inflam-
mation: A new approach for anticancer therapy. Frontiers in
Immunology,8(71). https://doi.org/10.3389/fimmu.2017.00071
Zhu, J., Wang, H., Chen, F., Fu, J., Xu, Y., Hou, Y., …Zhang, Q. (2016). An
overview of chemical inhibitors of the Nrf2‐ARE signaling pathway
and their potential applications in cancer therapy. Free Radical Biology
and Medicine,99, 544–556.
Zou, D. B., Wei, X., Hu, R. L., Yang, X. P., Zuo, L., Zhang, S. M., …Wang, Y.
(2015). Melatonin inhibits the migration of colon cancer RKO cells by
down‐regulating myosin light chain kinase expression through cross‐
talk with p38 MAPK. Asian Pacific Journal of Cancer Prevention,
16(14), 5835–5842.
How to cite this article: de Lima RMT, dos Reis AC, de
Menezes A‐APM, et al. Protective and therapeutic potential
of ginger (Zingiber officinale) extract and [6]‐gingerol in cancer:
A comprehensive review. Phytotherapy Research. 2018;1–23.
https://doi.org/10.1002/ptr.6134
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