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CHAPTER 12
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Resveratrol-Loaded Phytomedicines for
Management of Cancer
SHAKIR SALEEM, RUQAIYAH KHAN, and SANDEEP ARORA
shakir.saleem@chitkara.edu.in (S. Saleem)
ABSTRACT
Cancer has recently become one of the prominent reasons for human
mortality. Since ages, humans have used natural products to prevent illnesses
and this hints us that bioactive compounds are one of the best alternative
sources which can be employed in the prevention and treatment of various
kinds of diseases including cancer. Resveratrol, chemically known as
3,4,’5-trihydroxytrans-stilbene, is a non-flavonoid polyphenol phytoalexin
that naturally occurs in various species of plants, including peanuts, grapes,
pines, and berries. It has been used since ages in Chinese and Japanese traditional medicine to treat inflammation, headaches, cancers, and amenorrhea.
There are several reports of nanoformulations loaded with resveratrol has
potential anticancer activity including but not limited to cancer of stomach,
prostate, ovaries, alimentary canal, and breast. The nanoformulation of
resveratrol has also enhanced its bioavailability in humans. The stability
can be adjusted using several natural polymers, such as gelatin, PEG, and
PLGA, alone or in combination with synthetic polymers, like chitosan (CS)
and casein. Further studies are required to establish it as a potent clinical
anticancer agent.
;
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Cancer is one of the most commonly diagnosed diseases, and its related
morbidity and mortality constitute a very significant health problem worldwide. Since decades, great efforts are in process to discover an effective cure
but cancer persists as one of the prominent reasons for human mortality. It
has been estimated that by 2025, more than 2 million new cases of cancer
will be diagnosed, and more than 600,000 cancer-related mortality is
expected in the United States (Ko et al., 2017). There have been a multitude
of unique advances in the diagnosis and surveillance of cancer, nevertheless,
the overall survival rate for cancer has not bettered yet. Improved clinical
outcomes have been achieved through various individualized care medicines, including but not limited to targeted therapies (Okimoto et al., 2014).
But, some of the recent advances in cancer treatment ended up giving rise to
acquired resistance to many chemotherapeutic agents (Krepler et al., 2016).
The development of cancer is a multistep phenomenon involving
multifactorial processes where clear and discrete molecular and cellular
alterations can be seen. These cellular changes are distinct and have closely
connected phases of initiation, promotion, and progression of cancer (Hong
et al., 1997; Sethi et al., 2012; Chai et al., 2015). Development of resistance
is the prime concern of the current cancer therapies, which includes chemotherapy, targeted agents, radiation, surgery, and immunosuppression (Sethi et
al., 2009). The alternate way to encounter grave situations involving severe
cancer is to detect and diagnose early in the benign stage, this can help
in managing cancer in a better way giving more chances of survival. But
the even the diagnosis of cancer is not guaranteed with the latest trends in
diagnostics (Janakiram et al., 2016). The discovery of a lead molecule with
fervent anticancer activity and minimal side effects is the primary objective
in the ght against cancer.
Since ancient times, natural products have been used to prevent several
chronic diseases, including cancer (Shanmugam et al., 2011; Aggarwal et al.,
2009; Yang et al., 2013; Tang et al., 2014; Kannaiyan et al., 2011; Hsieh et al.,
2015; Bishayee et al., 2016; Shrimali et al., 2013). Bioactive compounds are
one of the best alternative sources which can be employed in the prevention
and treatment of various kinds of diseases including cancer (Shanmuugam
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et al., 2012, 2016, 2017, 2018; Prasannan et al., 2012). Phytochemicals like
phytoestrogens have been found to interfere with several cellular-signaling
pathways simultaneously, with no or minimal toxicity to normal cells
(Newman et al., 2016; Aggarwal et al., 2004). The application of substances
to prevent or delay the development of carcinogenesis has been termed
chemoprevention (Hong et al., 1997), and there is a burgeoning interest in
the use of natural compounds as possible chemopreventive and therapeutic
agents for human populations.
Resveratrol has been frequently reported as a potent anti-cancer agent
and this is why it has gained prominence recently (Aggarwal et al., 2004;
Bishayee et al., 2009, 2010; Sinha et al., 2016). Resveratrol, chemically
known as 3,4,’5-trihydroxy-trans-stilbene, is a non-avonoid polyphenol
phytoalexin that naturally occurs in various species of plants, including
peanuts, grapes, pines, and berries. It helps the plant to develop immunity
against the infection from different pathogens (Cucciolla et al., 2007).
Surprisingly, it has been used since ages in Chinese and Japanese traditional
medicine to treat inammation, headaches, cancers, and amenorrhea.
The stressful conditions like climatic vicissitude, ozone exposure, sunlight,
heavy metal, and infection to a pathogen like Botrytis cinerea leads to the
activation of stilbene synthase enzyme in plants which in turns produces
resveratrol (C
14H12O3
). It has two isoforms: trans-resveratrol (more stable)
and cis-resveratrol (Athar et al., 2007).
The trans-isoform is the major isoform of resveratrol and is also extensively
studied for several pharmacological actions. Trans-isoform is transformed
into cis isoform on exposure to heat and ultraviolet radiation. Resveratrol has
been classed as a phytoestrogen as its structure is like that of the synthetic
estrogen diethylstilbestrol. Its biological sources are very common as, resveratrol is easily available in common food items and augments health in ways
similar to viniferins, pterostilbene, and piceid (Jeandet et al., 2002). More-
over, few semi-synthetic resveratrol analogs were found to have specic
pharmacological benets like chemopreventive actions (Cai et al., 2004),
antioxidant effects (Colin et al., 2008) and anti-aging properties (Moran et
al., 2009). It had also been reported that resveratrol can reverse the resistance
to some drugs in different types and sizes of a tumor by over-sensitizing them
to chemotherapeutic agents (Mondal et al., 2016; Lee et al., 2016). Many
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pharmacological effects have been elucidated by the trans-resveratrol and
its glucoside including cardio-protective, anti-oxidative, anti-inammatory,
estrogenic, and anti-estrogenic, and anti-tumor activities (Stagos et al., 2012;
Carter et al., 2014). Additionally, the antimicrobial action (Stagos et al.,
2012) of trans-resveratrol was reported to be useful in the management of
cognitive impairments like dementia (Mazzanti et al., 2016; Molino et al.,
2016).
Resveratrol has broad-spectrum antimicrobial activity and has a widespectrum pharmacological activity like antioxidant and cardioprotective
functions. But it has been trending recently because of its outstanding anticancer as well as chemopreventive potential (Gupta et al., 2011). It has been
demonstrated that resveratrol can modulate many intracellular targets of
cancer, which inuence many vital processes like cell growth, inammation,
apoptosis, angiogenesis, cellular, and lymphatic invasion, and metastasis.
Resveratrol boosts the pro-apoptotic effects of cytokines (namely TRAIL),
chemotherapeutic agents, and gamma radiation (Athar et al., 2013).
Resveratrol is reported to possess multidimensional properties which
produce salubrious effects like anti-inflammatory, anti-oxidative, and antiaging qualities (Wadsworth et al., 1999; Ray et al., 1999; Baur et al., 2006).
It has also been found in red wine, and hence it is often hypothesized that
resveratrol is the prime element behind French Paradox, the minimized risk
of cardiovascular disorders in French people despite the high intake of saturated fats; which has been linked with high red wine consumption (Renaud et
al., 1992). Jang et al. in 1997 reported that resveratrol inhibits carcinogenesis
in a mouse-skin cancer model, and thereafter a resveratrol related publication
became superfluous. A multitude of research papers have reported the anticancer potential of resveratrol in human cell lines, including but not limited
to, myeloid, and lymphoid cancer cells, breast, skin, cervix, ovary, stomach,
prostate, colon, liver, pancreas, and thyroid cancer cells (Aggarwal et al.,
2004; Minamoto et al., 1999; Khansari et al., 2009; Barzilai et al., 2004).
Resveratrol has a grand role in preventing cancer and affects different stages
of cancer ranging from initiation and promotion to progression by interfering
and modulating the diverse signal-transduction pathways that monitor cell
growth, cell division, inflammation, apoptosis, metastasis, and angiogenesis.
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Many in vitro studies have examined the anti-proliferative and proapoptotic activity of resveratrol in human prostate cancer cells, and its mechanism
of action. It was found that the growth of LNCaP cells (hormone-sensitive
cells), DU-145 (androgen-independent) cells, and PC-3 (hormone-independent line possessing dysfunctional androgen receptors) cells were arrested
in a concentration-dependent manner. Resveratrol also antagonized the
formation of free radicals in macrophages and reduced the oxidative stress
within premalignant cells, and it decreased the production of NO in PC-3
and DU-145 cells, reducing growth and metastasis of prostate cancer (Ratan
et al., 2002).
Resveratrol-induced apoptosis in LNCaP and DU145 prostate cancer cell
lines through different PKC-mediated and MAPK dependent pathways (Shih
et al., 2004). Furthermore, resveratrol-mediated apoptosis is reported to be
associated with p53 activation and occurs by the death receptor Fas/CD95/
APO-1 in several human cancer cells (Athar et al., 2009). It is also assumed
that resveratrol exerts its chemopreventive action partially by interfering
with the expression or function of the androgen receptor (Ratan et al., 2002).
Resveratrol has a very interesting mechanism of chemoprevention, i.e., by
sensitization effect as reported by many in vitro and in vivo research studies,
resveratrol can overcome chemoresistance in tumor cells by regulating apoptotic pathways, downregulating drug transporters, downmodulating proteins
involved in the proliferation of tumor cell, and by inhibiting NF-κB and
STAT-3 pathway (Gupta et al., 2011).
Initiation of neoplasia occurs via alteration or mutation of genes spontaneously due to exposure to a carcinogenic agent, and finally resulting in mutagenesis (Minamoto et al., 1999). Reactive oxygen species (ROS) react with
the genetic material, DNA, and chromatin proteins, causing several types
of DNA damage (Barzilai et al., 2004; Fruehauf et al., 2007). In fact, the
chemical carcinogens must undergo phase-I biotransformation, especially
via cytochrome P450 enzyme to damage DNA in cells and transforms them
into reactive electrophiles. Additionally, the formation of carcinogen-DNA
adducts gives rise to chemical-induced carcinogenesis (Windmill et al.,
1997). This is irreversible initiation stage but can be stopped by inhibiting the
activity and expression of certain cytochrome P450 enzymes and enhancing
the activity of phase-II detoxification enzymes, which transform carcinogens
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Biomarkers as Targeted Herbal Drug Discovery
into less toxic and soluble products (Galati et al., 2000; Guengerich et al.,
2000) (see Table 12.1).
TABLE 12.1 Enlists the Anti-Tumor Activity of Resveratrol in Several Cell Lines and
Proposes the Mechanism of Action Followed
Activity Cell Line Mechanism of Action
Anti-tumor Human Leukemia
HL-60 cells
Human breast epithelial
Michigan cancer
foundation (MCF)-10A
cells
Human breast cancer
MCF-7 and liver cancer
HepG2 cells
Gastric cancer AGS Reduced TCDD-induced, AhR-mediated
cells CYP1A1 expression (Peng et al., 2009).
Human leukemia K562
cells
Suppressed free radical formation induced
by 12-O-tetradecanoylphorbol-13-acetate
(Windmill et al., 1997).
Scavenger of hydroxyls and superoxides, as
well as radicals induced by metals/enzymes
(Leonard et al., 2003).
Protects against lipid peroxidation within cell
membranes and damage to DNA resulting from
ROS (Leonard et al., 2003).
Inhibit 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD)–induced expression of cytochrome
P450 1A1 (CYP1A1) and 1B1 (CYP1B1),
as well as their catalytic actions (Chen et al.,
2004).
Abrogate the CYP1A activity induced by
environmental aryl hydrocarbon benzo[a]
pyrene (B[a]P) and catalyzed by directly
suppressing the CYP1A1/1A2 enzyme activity
and the signal-transduction pathway that
up-regulates the expression of carcinogenactivating enzymes (Ciolino et al., 1999).
Inhibition of TCDD-induced recruitment of
AhR and ARNT to the CYP1A1/1A2 and
CYP1A1/1B1 promoter and decreased their
expression (Beedanagari et al., 2009).
Increases both the activity and expression of
NAD (P)H: quinone oxidoreductase-1 (NQO1),
a carcinogen-detoxifying phase-II enzyme
(Hsieh et al., 2006).
Tumor promotion involves clonally enlarging initiated cells to create a
continuously proliferating, premalignant lesion. Tumor promoters are
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generally found to alter the expression of the gene, subsequently leading
to increased cellular proliferation and decreased cell death (Klaunig et
al., 2004). Studies conducted in vitro have revealed that resveratrol exerts
anti-proliferative activity by inducing apoptosis in cells. Of these, resveratrol modifies the balance of cyclins as well as cyclin-dependent kinases,
resulting in cell cycle inhibition at G0/G1 phase. For example, a link has
been found between the inhibition of cyclin D1/CDK4 by resveratrol and
cell cycle arrest in the G0/G1 phase within different cancer cells (Wolter
et al., 2001; Benitez et al., 2007; Bai et al., 2010; Gatouillat et al., 2010).
Resveratrol was also shown to elevate the levels of cyclin A and E, with
cell cycle seizure in the G2/M and S phases (Ferry-Dumazet et al., 2002;
Filippi-Chiela et al., 2011). Similar reports have specified that resveratrol causes the arrest of cell cycles and also causes the activation of the
p53-dependent pathway (Liao et al., 2010; Rashid et al., 2011; Hsieh et al.,
2011) (see Table 12.2).
TABLE 12.2 Describes the Mechanism of Action for Anti-Tumor Activity of Resveratrol in
Different Types of Cancer Cell Lines
Activity Cell Line Mechanism of Action
Anti-tumor
Promotion
Human skin cancer A431
cells
Breast cancer MCF-7 and
human prostate cancer
DU-145 cells
A549 cells S phase arrest, reduced retinoblastoma
HL-60 cells Modulating diverse signal transduction
Leukemic THP-1 cell line Induces Fas-independent apoptosis (Tsan et
Leukemia CEM-C7H2 cells Induces Fas-independent apoptosis
Downregulating the expression of cyclin
D1, cyclin D2, and cyclin E.
Inhibiting the activities and/or expression
of CDK2, CDK4, and CDK6.
Upregulating the expression of p21 (Gartel
et al., 2002).
Modulating CDK4 and cyclin D1
expression (Kim et al., 2003a).
protein (Rb) phosphorylation, and induced
p21 and p53 protein expression (Kim et al.,
2003b).
pathways via regulation of the levels of
Fas and Fas-ligand and inducing apoptosis
(Clement et al., 1998; Delmas et al., 2003).
al., 2000).
(Bernhard et al., 2000).
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