A review
acknowledged to all directly or indirectly related to this review.
Source : from literature on Flavonoids
Sanjeet Kumar
Ravenshaw University
sanjeet.biotech@gmail.com
Human
beings are always suffered from various types of disorders and microbial
infections since primitive due to an-appropriate life styles. The diseases give
attention towards the interest in finding curing agents. The primitive man
found the curing agents from two main sources, Plant Kingdom and Animal Kingdom
and started the therapeutic practices. They learned the potentials of
particular agents against specific disorders / microbial infections from
generation to generation. These two sources have unique self defence properties
which indicate the presence of some bioactive compounds. Those bioactive
compounds are major constituents in therapeutic practices is known as
therapeutic agents. This therapeutic agent is known as “secondary metabolites”.
Secondary metabolites are directly proportional to therapeutic potentials of
the source agents. Among the sources, plants are principle due to possess
different types of secondary metabolites, such as alkaloids, terpenoids, glycosides,
phenols, flavonoids, polyphenols, steroids etc. Among them, flavonoids and
their derivatives are very important. They are very effective in lethal
diseases like cancer, aging, atherosclerosis, ischemic injury, inflammation,
and neurodegenerative diseases (parkinson’s and Alzheimer’s) etc. Globally,
these lethal deceases represent a substantial burden in the community and
appear to be a prime cause of concern. Among all, Cancer is very dangerous for
human.
A human adult comprises about 1015 cells; scores of
them divide and differentiate in order to refurbish organs and tissues, which
require cell turnover. However, if the cells do not stop dividing, they may
lead to cancer. Characteristically, cancer is an unrestrained proliferation of
cells which become structurally abnormal and possess the ability to detach them
from a tumour and establish a new tumour at a remote site within the host.
Every year over 200,000 people are diagnosed with cancer in the United Kingdom only,
and approximately 120,000 die as an aftermath of the disease. According to the International
Agency for Research on Cancer, in 2002, cancer killed > 6.7 million people
around the world and another 10.9 million new cases were diagnosed4. If the
results are extrapolated, at the same rate, an estimated 15 million people will
have cancer, annually, by 2020. According to an estimate given by American
Cancer Society, about 1,500,000 new cases and over 500,000deaths are expected
in the US by 2009. The National Cancer Registry of South Africa has spotted the
cancers of bladder, colon, breast, cervix, lungs and melanoma commonly
amonginhabitants. Attempts are underway to work out the therapeutic and anti
neo plastic properties of medicinal plants. Plant bioactive compound is a
potential source for antitumor and cytotoxic activities. Consequently, herbal
medicines have received much attention as substitute anticancer drugs. Cancer
is a major public health problem in many countries of the world.1 Because of this;
the disease receives the special attention of the World Health Organization
from the International Agency for Research on Cancer.
The GLOBOCAN-2008 project was one of the tools
created by these international agencies that allowed estimation of the cancer incidence
and mortality. The program indicated that about14.9 million cancer cases and
8.9 million cancer deaths are estimated to occur in 2015 worldwide, with the
majority of deaths occurring in the economically developing world.2In recent
decades, the disease has become more common in developing countries, such as
Brazil, where it is estimated there has been more than 500000 new cases of
cancer in 2013. Natural products are privileged structures created by strong biological
and ecological pressure that are able to interact with a wide variety of
biological targets, consequently originating effective drugs in a large variety
of therapeutic indications.4,5Throughout human evolution, the importance of
natural products for medicine and health has been enormous, from the earliest
civilizations until today. The accumulated experience, knowledge and research
over the years makes the secondary metabolites from natural sources, like
plants, the most consistently successful approach for obtaining modern
Medicines.
Therefore
an attempt has been made to gather the information about anti-cancer activity
of Flavonoids as mini review.
In 1930, a new substance
was isolated from oranges that can reduce the capillary permeability and is
believed to be a member of a new class of vitamins hence designated as vitaminP,
however, later on this substance was identified as a flavonoid (rutin).
Flavonoids drew greater attention with the decreased incidence of cardiovascular
diseases, in spite of a greater saturated fat intake in Mediterranean
population, which was associated with red wine consumption (Renaud and de
Lorgeril 1992). Flavonoids belong to a very vast group of plant secondary
metabolites with variable phenolic structures and are found in fruits,
vegetables, grains, bark, roots, stems, flowers, tea and wine (Nijeveldt et al.
2001). In plants, flavonoids are performing a variety of functions including pollination,
seed dispersal, pollen tube growth, resorption of mineral nutrients, tolerance
to abiotic stresses, protection against ultraviolet and allelopathic
interactions, etc. (Samanta et al. 2011; Hassan and Mathesius 2012). More than
8,000 different compounds of polyphenols have been known and that can be
further subdivided into ten different general classes (Ververidis et al. 2007;Harborne
and Williams 2000; Chahar et al. 2011). Flavonoids are part of this family and
have more than 4,000 varieties (Harborne 1994). Isoflavonoids (phytoestrogens
or non-steroidal estrogens) such as the soy isoflavones—genistein and daidzein,
have also been known for their therapeutic significance particularly in the
protection of human health (Wiseman et al. 2000; Stevens and Page 2004; Orgaard
and Jensen 2008; Xiao 2008; Ogbuewu et al. 2010;Wiseman et al. 2002). There are
a variety of factors such as species, variety, climate, degree of ripeness and
post harvest storage which influence the concentration of flavonoids in foods
(Holland et al. 1995; Robards and Antolovich 1997; Pascual Teresa et al. 2000;
Modak et al. 2011). Flavonoids have a remarkable reducing ability and ability
to interact with proteins (Haslam1996; Havsteen2002; Liu et al. 2010; McRae and
Kennedy 2011). This review focus on biochemical studies carried out to analyze
the possible health effects of flavonoids and to assess their potential in the
prevention of degenerative diseases or their therapeutic value as potential
drugs.
Polyphenolic terpenoids
are the most extensively studied flavonoids which have a characteristic
C6–C3–C6 structure. The chemical structure of flavonoids is based on a C15 skeleton
with a CHROMANE ring bearing a second aromatic ring B in position 2, 3 or
4.They have been further subdivided into flavones, flavonols, flavanones, flavanols,
anthocyanins and isoflavones based on the nature of C3 element (Fig. 1).
Different groups of flavonoids and their dietary sources are mentioned in Table
1. Flavonoids, especially flavanols, flavonols and anthocyanins are relatively
abundant in humandiet and possibly involved in prevention of cancers, cardiovascular
diseases and neurodegeneration (Bazzano et al.2002; Clifford 2004; Atmani et
al. 2009; Fang et al. 2010; Xiao et al. 2011).
The flavonoids are formed
in plants and participate in the light-dependent phase of photosynthesis during
which they catalyze electron transport (Das 1994). They are synthesized from
the aromatic amino acids phenylalanine and tyrosine, together with acetate
units (Heller and Forkmann 1993). Phenylalanine and tyrosine are converted to
cinnamic acid and parahydroxycinnamic acid, respectively, by the action of
phenylalanine and tyrosine ammonia lyases (Wagner and Farkas 1975). Cinnamic
acid (or parahydroxycinnamic acid) condenses with acetate units to form the cinnamoyl
structure of the flavonoids (Fries rearrangement). A variety of phenolic acids,
such as caffeic acid, ferulic acid, and chlorogenic acid, are cinnamic acid derivatives.
There is then alkali catalyzed condensation of an ortho-hydroxyacetophenone
with a benzaldehyde derivative generating chalcones and flavonones (Fig. 2), as
well as a similar condensation of an ortho-hydroxyacetophenone with a benzoic
acid derivative (acid chloride or anhydride), leading to 2-hydroxyflavanones
and flavones (Heller and Forkmann 1993). The synthesis of chalcones and
anthocyanidins has been described in detail by Dhar (1994). Biotransformation
of flavonoids in the gut can release these cinnamic acid (phenolic acids) derivatives
(Scheline 1991). In terms of their biosynthesis, the phenyl propanoid pathway
produces a range of secondary metabolites such as phenolic acids, lignins, lignans
and stilbenes using phenyl alanine and tyrosine as the precursor. After
tannins, flavonoid glycosides are by far the most common dietary sources of
flavonoids. Usually 110–121 mg/day of flavonoids
has been recommended as a healthy diet for an adult (Hertog et al. 1992,1993a,
1993b).
The fate of orally and
parenterally administered flavonoidsin mammals was reviewed by Griffiths and
Barrow (1972) and later by Hollman and Katan (1998). Considerable information
is available regarding the metabolism of flavonoids in animals and to a very
limited extent inhumans (Hackett 1986; Scheline 1991). Hertog et al. (1992)
measured the content of potentially anti-carcinogenic flavonoids of 28 vegetables,
wine, and fruits frequently consumed in The Netherlands and the measured flavonoids
were quercetin, kaempferol, myricetin, apigenin, and luteolin. The mean daily intake
of these five antioxidant flavonoids was 23 mg/day, which exceeds the intake of
other familiar anti-oxidants such as b-carotene(2–3 mg/day) and vitamin E (7–10
mg/day) and is about one-third the average intake of vitamin C (70–100 mg/day) (Hertog
et al. 1993b). Quercetin is the most important contributor to the estimated
intake of flavonoids, mainly from the consumption of apples and onions (Knekt
et al. 1996; Gibellini et al. 2011; Giuliani et al. 2008). It is extremely
difficult to estimate the daily human intake of flavonoids, especially because
of the lack of standardized analytical methods (Scalbert and Williamson 2000). However,
the average daily intake of the most abundant flavonoids, catechins, is *100 mg
(Perez-Vizcaino et al. 2009). Similar to daily intake, it is also quite complex
to assess and quantify the bioavailability of flavonoids (Russo 2007). In
countries such as Japan, Korea, China, and Taiwan, the mean daily intake of soy
products has been estimated to be in the range of 10–50 g compared to only 1–3
g in the United States (Messina et al. 1994). Flavonoid pharmacokinetics is
complex, since they are usually contained as glucosides in fruits and
vegetables, cleaved and glucuronated during uptake. Glucuronides may be metabolized,
or stored or set free as aglycones by tissuespecific glucuronidases; thus,
plasma concentration may not always be a good measure of bioavailability
(Seelinger et al. 2008). Most flavonoids, except catechins, exist in nature as glycosides.
Moreover, at least quercetin glucosides were absorbed better than the aglycone
quercetin-bglucoside (Hollman and Katan 1998). Finally, supplementation of the
diet should more appropriately use flavonoid glycosides instead of aglycones.
However, this has been questioned by other researchers (Manach et al. 1997). The
role of flavonoid glycosylation in facilitating absorption is questioned by the
fact that catechin, which is not glycosylated in nature, is absorbed relatively
efficiently (Okushio et al. 1996). Because the half-lives of conjugated flavonoids
are rather long (23–28 h) (Young et al. 1999), accumulation may occur with
regular intakes, which may in turn result in sufficiently active flavonoid
concentrations (Nijeveldt et al. 2001). Flavanoid bioavailability and the mechanism
by which flavonoids are absorbed from intestine and metabolized via microbial
catabolism, conjugation in liver and enterocytes have been studied by a number
of workers (Hollman and Katan 1999; Scalbert and Williamson 2000, Hollman 2004;
Passamonti et al. 2009). Studies in human and animals have indicated that some (for example cinnamate conjugates, flavanols,
quercetin glucosides) can be absorbed in the small intestine (Olthof et al.
2000, 2003; Nardini et al. 2002; Cermak et al. 2004) while quercetin, quercetin
galactoside, rutin, naringenin- 7-glucoside and many others are not. Mechanismbof
absorption has not been completely elucidated while the membrane transport of
flavonoids is a fundamental part of their bioavailability in both plant and
animal organisms, and current knowledge suggests the involvement of both ATP-dependent
pumps and ATP-independent transporters (Passamonti et al. 2009). Depending on
PPT subclass, only 5–10 % of amount consumed is absorbed in small intestine and
major part of that absorbed in the duodenum enters the circulation as methylated,
sulfate-conjugated, glucuronide-conjugated and glycine-conjugated forms (Kroon
et al. 2004). The rest 90–95 % of total PPT ingested plus any mammalian
glucuronide excreted through bile pass to the colon where they are metabolized
by gut microflora. may be extensive, and
include the removal of sugars, removal of phenolic hydroxyls, fission of
aromatic rings, hydrogenation, and metabolism to carbon dioxide, possibly via oxaloacetate
(Walle et al. 2001). A substantial range of microbial metabolites has been
identified, including phenols and aromatic acids, phenolic acids, or lactones
possessing 0, 1, or 2 phenolic hydroxyls and up to five carbons in the side
chain (Clifford and Brown 2006). The elimination half-lives are very variable,
ranging from as low as 1 h (Meng et al. 2001) to values in excess of 20 h
(Olthof et al. 2003).
A huge number of epidemiological studies have been conducted
to prove the protective effect of flavonoids against cancer. Increased
consumption of lignans and greater plasma concentrations of their metabolites
have been linked with reduced incidence of estrogen-related cancers in some
(Pietinen et al. 2001; Dai et al. 2002; Boccardo et al. 2004; McCann et al.
2004) but not all studies, (Kilkkinen et al. 2004; Zeleniuch-Jacquotte et al. 2004)
and a prospective study was equivocal (den Tonkelaar et al. 2001). It has been
suggested that this might have a
genetic basis (McCann et al. 2002). Increased consumption of isoflavones has
also been associated with decreased risk of estrogen-related cancers and
vascular diseases (Arai et al. 2000; Birt et al. 2001). from four cohort
studies and six case–control studies, which have examined associations of
flavonoid intake with cancer risk revealed that flavonoids, especially
quercetin, may reduce the risk of lung cancer in two studies but a
nonsignificant increased risk in a third study. High versus low quercetin and
kaempferol intakes were associated with 40 and 50 % reduction in risk,
respectively, for stomach cancer. There was no statistically significant
association of any flavonoids with either bladder cancer or breast cancer risk
(Neuhouser 2004). In a network of multicentric Italian case–control studies
including about 10,000 incident, histologically confirmed cases of selected
cancers and over 16,000 controls, the association of flavonoids,
proanthocyanidins and cancer risk was evaluated by Rossi et al. (2010). It was
found that total flavonoids, flavanones, and flavonols were inversely related
to oral and laryngeal cancers (ORs, respectively, 0.56 and 0.60 for total
flavonoids; 0.51 and 0.60 for flavanones; and 0.62 and 0.32 for flavonols).
Flavonols were also inversely related to laryngeal cancer (OR 0.64), whereas
flavanones were inversely related to esophageal cancer (OR 0.38). A reduced
risk of colorectal cancer was found for high intake of anthocyanidins (OR
0.67), flavonols (OR 0.64), flavones (OR 0.78), and isoflavones (OR 0.76).
Inverse relations with breast cancer were found for flavones (OR 0.81) and flavonols
(OR 0.80). Flavonols (OR 0.63) and isoflavones (OR 0.51) were inversely
associated to ovarian cancer, flavonols (OR 0.69) and flavones (OR 0.68) were inversely
associated to renal cancer. No association between flavonoids and prostate
cancer emerged, whereas inverse association was found between
proanthocyanidins (Rossi et al. 2010). The
intake of flavonoids is not inversely related with bladder cancer or breast
cancer risk in some of the studies (Garcia-Closas et al. 1999; Peterson et al.
2003). Quercetin has been reported to prevent renal cell cancer among male smokers
(Wilson et al. 2009). A case–control study conducted between 1994 and 2002 in
four Italian areas to study the relation between major flavonoid classes and
renal cell carcinoma by Bosetti et al. 2007 revealed that flavonols and
flavones were inversely related to the risk of renal cancer. A cohort of 34,651
postmenopausal cancer-free revealed inverse relation between catechin intake and
rectal cancer (Arts et al. 2002). Population-based case–control studies carried
out separately in Hawaii, Uruguay and Spain suggested an inverse association
between different cancers (oral cavity, pharynx, larynx and esophagus, lungs,
stomach) and total intake of flavonoids, beta-carotene and vitamin E (Le
Marchand et al. 2000; Stefani et al. 1999a, b; Garcia-Closas et al. 1999). Inverse
association of cholangiocarcinomas (CAC) with flavan-3-ols, anthocyanidins and
total flavonoids has been reported and flavones may be inversely associated
with hepatocellular carcinoma cells (HCC) risk (Lagiou et al.). A statistically
significant association between highest intake and reduced risk of developing
lung cancer has been reported whereby an increase in flavonoidintake of 20
mg/day was associated with a 10 % decreased risk of developing lung cancer
(Tang et al. 2009).The studies on tea, flavonoids and lung cancer risk indicated
a small beneficial association, particularly among never-smokers. More well-designed
cohort studies are needed to strengthen the evidence on effects of long-term exposure
to physiological doses of dietary flavonoids (Arts 2008). Consumption of soy
foods rich in isoflavones has been weakly associated with reduced colon and
prostate cancer (Adlercreutz 2002; Guo et al. 2004; Holzbeierlein et al. 2005;
Goetzl et al. 2007). A protective effect of flavonoids in association with
vitamin C has been shown on esophageal cancer using data from case–control
study conducted in northern Italy (Rossi et al. 2007). Flavonoid rich diet may
decrease pancreatic cancer risk in male smokers not consuming supplemental
alpha-tocopherol andbeta-carotene (Bobe 2008).
Isoflavonoids have biphasic effects on the
proliferation of breast cancer cells in culture; at concentrations [5mM, genistein
exhibits a concentration-dependent ability toinhibit both growth factor-stimulated
and estrogen-stimulated(reversed by 17b-estradiol) cell proliferation (So et
al.1997). Although genistein is a much better ligand for ERb than for the ERa
(20-fold higher binding affinity) (Kuiper et al. 1997), it can also act as an
estrogen agonist via both ERa and ERb in some test systems (Kuiper et al. 1998;
Mueller et al. 2004). Furthermore, although genistein binds to the
ligand-binding domain of ERb in a manner similar to that observed for 17b-estradiol,
in the ERb–genistein complex the AF-2 helix (H12) does not adopt the normal agonist
type position, but instead takes up a similar orientation to that induced by ER
antagonists such as raloxifene (Pike et al. 1999). This suboptimal alignment of
the transactivation helix is in keeping with the reported partial agonist
activity of genistein via ERb in human kidney cell (Barkhem et al. 1998). Anti-cancer
activity of methanolic flower extract of Tecoma stans (METS) was evaluated by
both in vitro (Vero and Hep 2 cell lines) and in vivo (using Ehrlich ascites carcinoma
tumor model) methods and compared with 5-flurouracil. A significant
dose-dependent anti-tumor activity was indicated (Kameshwaran et al. 2012).
Enriched ginger extract exhibited higher anti-cancer activity on MCF-7 breast
cancer cell lines with IC 50 value 34.8 and 25.7 lg/ml for two varieties. IC50
values for MDA-MB- 231 were 32.5 and 30.2 lg/ml for rhizome extract of two varieties
(Rahman et al. 2011). Luteolin-7-methyl ether isolated from leaves of Blumea
balsemifera showed strong cytotoxicity against human lung cancer cell lines
(NCIH187) with IC 50 of 1.29 lg/ml and moderate toxicity against oral cavity
cancer cell lines (KB) with IC 50 of 17.83 lg/ml (Saewan et al. 2011). In vitro
and in vivo studies on anti-cancer activity of flavonoids isolated from a
herbal formulation revealed IC 50 of 24.948, 31.569 and 6.923 lg/ml,
respectively, on three cancer cell lines MCF-7, Hep G-2 and ES-2 with dose-dependent
inhibitory effect on hepatocellular carcinoma in mice (Liu et al. 2011).
Broccolini leaf flavonoids (BLF) possess a dose-dependent anti-proliferative
effects on four human cancer cell lines (SW480, HepG2, Hela, and A549) and
apoptosis induction activity on SW480 cell line. Thus, the hybrid species Broccolini
could be considered as a functional vegetable with potential in assisting for
the treatment of four human cancers examined (Wang andZhang 2012). Apigenin
inhibited skin papillomas and showed the tendency to decrease conversion of
papillomas to carcinomas (Wei et al. 1990). Luteolin has been shown to
penetrate into human skin, making it also a candidate for the prevention and
treatment of skin cancer (Seelinger et al. 2008). Seufi et al. (2009) demonstrated
that preventive effect of quercetin on hepato carcinomas in rats by RAPD-PCR,
whereby, it was proved that quercitin exerted a preventive effect via decreased
oxidative stress and decreased antioxidant activity. Dietary proanthocyanidins
mostly present in apples, pears and pulses has been suggested to reduce the risk
of pancreatic cancer by 25 % (Rossi et al. 2010). Ethanolic extract of propolis
has been found to inhibit urinary bladder transitional cell carcinoma (TCC)
cell proliferation with no cytotoxic effect on normal epithelial cells
(Orsˇolic´ et al. 2010). Genistein inhibited the expression of micro-RNA 21 in
A-498 (RCC) cells and in the tumors formed after injecting genistein treated
A498 cells in nude mice besides inhibiting tumor formation (Zaman et al. 2012).
Kaempferol, a dietary flavonoid is effective in reducing vascular endothelial
growth factor (VEGF) expression in ovarian cancer cells. It enhances the effect
of cisplatin ovarian cancer cells (Luo
et al. 2010). The growth of U14 cervical cancer could be inhibited by
Scutellaria baicalensis total flavonoids (STF), the cell proliferation
inhibited by arresting cell cycle and cell apoptosis induced by regulating the
expression of Bax and Bcl-2 gene by treatment of STF (Peng et al. 2011). Some
of the Indian medicinal plants like Ashwagandha, Curcumin, Lithosprmum radix, green
tea, Chinese herb Astragalus and Japanese herb Juzen- Taiho-To have been reported
to be effective against various cell lines of lung cancers (Ravichandiran et
al. 2011). A comparison of cytotoxic effect of 11 flavonoids on chronic myeloid
leukemia K562 cells and peripheral mononuclear cells indicated that baicalein
and myricetin had a specific cytotoxic effect on leukemia cells (Romanouskaya
and Grinev 2009). Apoptotic activity of 22 flavonoids and related compounds in
leukemic U937 cells were tested by Monasterio et al. (2004). They reported that
flavones but none of the isoflavones induced the apoptotic cell death as
determined by reduction in cell viability, flow cytometery and DNA fragmentation. The molecular consequences of
apigenin treatment in myeloid and erythroid subtypes reveal the blocked proliferation
of both cell lines through cell cycle arrest in different phases. JAK/STAT was
one of the major target of apigenin but at the same time apigenin reduced susceptibility
toward the commonly used therapeutic agent vincristine (Ruela-de-Sousa et al. 2010).
A newly synthesized flavonoid III-10 could express anti-cancer effect on human
U937 leukemia cell line through differentiation induction. The
differentiation-related proteins phospholipids scramblase 1 (PLSCR1) and promyelocytic
protein (PML) were upregulated after III-10 treatment through activation of
protein kinase Cd (Qin et al. 2012). Quercetin inhibited thyroid cell growth in
association with inhibition of insulin-modulated-PI3- Kinase-AKT kinase
activity. It also decreased TSH-modulated RNA level of NIS (sodium iodide
sympoter) gene and thereby suggested to be a novel disrupter of thyroid function
which has potential uses in thyroid cancers (Giuliani et al. 2008). Chrysin inhibited
proliferation of HTH 7 and KAT 18 (anaplastic thyroid cancer cell lines) in a
dose and time-dependent manner. A significant increase in cleaved caspase-3, cleaved
polyADP ribose polymerase (PARP) along with a decrease in cyclin D1, Mcl-1 and XIAP
was observed (Phan et al. 2011). BNF (b-napthoflavone) showed a moderate
anti-proliferative activity in WHCO-6 cells and a weak activity in WHCO-1
cells. It resulted in differential expression of CYP1A1, CYP1A2 and CYP1B1
(Molepo 2010).
Conclusions
Flavonoids greatly influence the cascade of immunological
events associated with the development and progression of cancer. One has to
understand the mechanism how these flavonoids get accumulated in cellular
organelles and tissues once they enter inside. Flavonoids have the potential of
modulatng many biological events in cancer such as apoptosis, vascularization,
cell differentiation and cell proliferation. A strong correlation persists
between flavonoid-induced modulation of kinases with apoptosis, cell proliferation
and tumor cell invasive behavior in vitro. Also, some of the dietary flavonoids
have been known to display in vivo anti-tumor activity and repress in vivo angiogenesis.
The cross talk between flavonoids and the key enzymes related to neoplastic
cells and metastasis has to be understood in vitro and in vivo as well,
providing new insights for fighting against cancer.
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