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Sharmila Shankar - Nutrition, Diet and Cancer

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Sharmila Shankar Nutrition, Diet and Cancer

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Sharmila Shankar and Rakesh K. Srivastava (eds.) Nutrition, Diet and Cancer 2012 10.1007/978-94-007-2923-0_1 Springer Science+Business Media B.V. 2012
1. Aberrant Signaling Pathways in Cancer: Modulation by the Dietary Flavonoid, Quercetin
Ramamurthi Vidya Priyadarsini 1 and Siddavaram Nagini 1
(1)
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
Siddavaram Nagini
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Abstract
Of late, flavonoids, a class of polyphenolic compounds ubiquitously present in the human diet have gained increasing attention in cancer prevention. Defining the anti-cancer mechanisms of quercetin, a major dietary flavonoid has been the topic of intense research over the last two decades. Evidences from experimental studies have shown that quercetin not only offers protection against chemically induced cancers but also suppresses the growth of cancer cells in vitro and in vivo by enhancing carcinogen detoxification and antioxidant defences, inducing cell cycle arrest and apoptosis, inhibiting matrix invasion and angiogenesis, and modulating intracellular signalling circuits. Epidemiological studies across different populations have also indicated that quercetin intake is associated with reduced risk of various cancers. This review summarizes the preclinical and clinical data on the anti-cancer effects of quercetin, the key molecular mechanisms of action, its synergistic interactions, and adverse side effects to warrant further clinical evaluation of quercetin for cancer prevention and therapy.
Introduction
Cancer, a multifactorial heterogeneous disease, is a major cause of morbidity and mortality worldwide (Jemal et al. ). Thus targeting multiple molecular pathways that are prone to deregulation during carcinogenesis is the major focus in cancer prevention and treatment.
Cancer chemoprevention as defined by Sporn et al. (). In particular flavonoids, a group of polyphenolic compounds have gained consideration as potential chemopreventive agents.
Flavonoids
Flavonoids are a class of naturally occurring polyphenolic compounds, ubiquitously present in fruits, vegetables, nuts, and in beverages such as tea, coffee, and wine. Over 5,000 different flavonoids have been identified so far. Most flavonoids possess a common phenylbenzopyrone structure (C6C3C6) and are sub-divided into various classes such as flavones, isoflavones, flavonols, flavanols, and flavanone based on the saturation level and opening of the central pyran ring. Human dietary intake of flavonoids is estimated to be around few hundreds of mg/day. Despite their poor solubility in water and rapid rate of metabolism and degradation, the flavonoids are recognized to confer a myriad health benefits (Clere et al. ).
Fig 11 Chemical structure of quercetin Quercetin consists of a basic - photo 1
Fig. 1.1
Chemical structure of quercetin. Quercetin consists of a basic flavonoid structure with three rings A , B and C and 5 hydroxyl groups. The rings A and B are aromatic, and ring C is heterocyclic. The hydroxyl groups are found at 3, 3, 4, 5 and 7 positions
Quercetin
Quercetin (3,3,4,5,7-pentahydroxyflavone), commonly found in apples, onions and green tea occurs mainly as a glycoside bound to one of the hydroxyl groups of the flavonol. Structurally, quercetin consists of two aromatic and one heterocyclic ring (Fig. ).
Evidence of Anticancer Effects
Accumulating data from various experimental and epidemiological studies have provided substantial proof for the anticancer effects of quercetin.
In vitro
Numerous studies have demonstrated the anti-cancer effects of quercetin on diverse cell systems. Quercetin was shown to inhibit the growth of human cervical cancer (HeLa) cells, and human leukemia HL-60 cells by inducing apoptosis (Vidya Priyadarsini et al. ).
In vivo
A substantial number of in vivo studies on various animal tumor models has provided evidence that quercetin inhibits carcinogenesis by interfering with the initiation, promotion, as well as progression stages of carcinogenesis (Pereira et al. ) demonstrated that dietary administration of quercetin inhibited tumour promotion in the small intestine in a medium-term multi-organ carcinogenesis model.
An analogue of quercetin was shown to interfere with tumor development in Apc (Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice models of colorectal carcinogenesis (Howells et al. summarizes the anticancer effects of quercetin in vitro and in vivo .
Table 1.1
Summary of the anticancer effects of quercetin in vitro and in vivo
Type of study
Cell line/Animal tumor model
Mechanisms
Reference(s)
In vitro
Human breast cancer cells, MDA-MB-231
Increasing cytosolic Ca2+ levels
Choi et al. ()
Reducing mitochondrial transmembrane potential
Activation of caspase-3, -8 and 9
Upregulation of Bax and AIF
Downregulation of Bcl-2
Human cervical cancer cells, HeLa
Modulation of cell cycle regulatory proteins
Vidya Priyadarsini et al. ()
Inhibition of NF-B activation
Induction of G2/M cell cycle arrest
Upregulation of bax, cytochrome C, Apaf-1 and caspases
Downregulation of Bcl-2 and survivin
Human colon adenocarcinoma cells (CO115, CaCo-2)
Induction of cell cycle arrest
Murtaza et al. ()
Modulation of -catenin and MAPK signaling
Downregulation of cell cycle associated genes
Upregulation of tumor suppressor genes
Human leukemia cells, HL-60
Upregulation of FasL through activation of ERK and JNK
Lee et al. ()
Activation of caspase-8 and Bid cleavage
Induction of extrinsic apoptosis
Promotion of histone H3 acetylation
Human lung cancer cells, NCI-H209
Induction of G2/M phase cell cycle arrest
Hung ()
Upregulation of cyclin B, Cdc25c-ser-216-p and Wee1
Induction of apoptosis via caspase-3 cascade
Human non-small cell lung cancer cells, NSCLC
Upregulation of death receptor-5 expression
Chen et al. ()
Suppression of survivin expression
Blockade of serine/threonine kinase Akt activity
Human ovarian cancer cells, OVCAR-3
Inhibition of cell proliferation
Luo et al. ()
Decreased VEGF expression
Table 1.1
(continued)
Type of study
Cell line/Animal tumor model
Mechanisms
Reference(s)
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