FLAVONOIDS: POTENT ANTI-CANCER AGENTS

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.

Adlercreutz H (2002) Phyto-oestrogens and cancer. Lancet Oncol 3:32–40.

Agullo G, Gamet-Payrastre L, Manenti S, Viala C, Re´me´sy C, Chap and inhibition of phosphatidylinositol-3 kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol 53(11):1649–1657.

Aherne AS, Obrien NM (2002) Dietary flavonols: Chemistry, foodcontent and metabolism. Nutrition 18: 75–81.

Ahmad N, Mukhtar H (2004) Cytochrome P450: a target for drugdevelopment for skin diseases. J Investig Dermatol 123:417–425

Ahn SC, Kim GY, Kim JH, Baik SW, Han MK, Lee HJ, Moon DO, Lee CM, Kang JH, Kim BH, Oh YH, Park YM (2004) Epigallocatechin-3-gallate, constituent of green tea, suppresses the LPS-induced phenotypic and functional maturation of murine dendritic cells though inhibition of mitogen-activated-protein kinases and NF-kB. Biochem Biophys Res Commun 313: 148–155

Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y (1987) Genistein, a specific inhibitor of tyrosine specific protein kinase. J Biol Chem 262:5592–5595

Alvarez AI, Real R, Perez M, Mendoza G, Prieto JG, Merino G (2010) Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response. J Pharm Sci 99:598–617

Amin AR, Kucuk O, Khuri FR, Shin DM (2009) Perspectives for cancer prevention with dietary compounds. J Clin Oncol 27(16):2712–2725

Amin AR, Thakur VS, Paul RK, Feng GS, Qu CK, Mukhtar H, Agarwal ML (2007) SHP-2 tyrosine phosphatase inhibits p73-  dependent apoptosis and expression of a subset of p53 target genes induced by EGCG. Proc Natl Acad Sci USA 104:5419–5424

Anzenbacher P, Anzenbacherova´ E (2011) Cytochromes P450 andmetabolism of xenobiotics. Cell Mol Life Sci 58(5–6):737–747

Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N (2000) Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130(9): 2243–2250

Arnold RS, He J, Remo A, Ritsick D, Yin-Goen Q, Lambeth JD, Datta MW, Young AN, Petros JA (2007) Nox1 expression determines cellular reactive oxygen and modulates c-fos inducedgrowth factor, interleukin-8, and Cav-1. Am J Pathol 171(6): 2021–2032

Arts IC, Hollman PC (2005) Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 81:317S–325S

Arts IC, Jacobs DR, Gross M, Harnack LJ, Folsom AR (2002) Dietarycatechins and cancer incidence among postmenopausal women:the Iowa Women’s Health Study (United States). Cancer Causes Control 13:373–382

Arts ICW (2008) A review of the epidemiological evidence on tea, flavonoids, and lung cancer. J Nutr 138:1561S–1566S

Atkinson C, Warren RML, Sala E, Dowsett M, Dunning AM, Healey CS, Runswick S, Day NE, Bingham SA (2004) Red cloverderived isoflavones and mammographic breast density: a doubleblind, randomized, placebo-controlled trial. Breast Cancer Res 6:R170–R179

Atmani D, Chaher N, Atmani D, Berboucha M, Debbache N, Boudaoud H (2009) Flavonoids in human health: from structure to biological activity. Curr Nutr Food Sci 5:225–237

Bagli E, Stefaniotou M, Morbidelli L, Ziche M, Psillas K, Murphy C, Fotsis T (2004) Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 30-kinase activity. Cancer Res 64:7936–7946

Balasuriya BWN, Rupasinghe HPV (2011) Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of  hypertension. Funct Foods Health Dis 5:172–188

Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson JA, Nilsson S (1998) Differential response of estrogen receptor a and estrogen receptor b to partial estrogen agonists/antagonists. Mol Pharmacol 54:105–112

Barnes S (1998) Phytoestrogens and breast cancer. Ballieres Clin Endocrinol Metab 12:559 -579

Bazzano LA, He J, Ogden LG, Loria CM, Vupputuri S, Myers L, Whelton PK (2002) Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. A J Clin Nutr 76(1):93–99

Bazzoli DL, Hill S, DiSilvestro RA (2002) Soy protein antioxidant actions in active, young adult women. Nutr Res 22:807–815

Beecher GR. 'Overview of Dietary Flavonoids: Nomenclature, Occurrence and Intake'. J Nutr2003; 133:248-254.

Benavente-Garcia O, Castillo J, Marin, FR, Ortuno A, Del-Rio JA(1997) Uses and properties of citrus flavonoids. J Agric Food Chem 45: 4505-4015.

Birt DF, Hendrich S, Wang W (2001) Dietary agents in cancerprevention: flavonoids and isoflavonoids. Pharmacol Ther 90:157–177

Blagosklonny MV (2001) Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy- induced apoptosis in multidrug-resistant cells but protects normal cells. Leukemia 15:936–941

Bobe G (2008) Flavonoid intake and risk of pancreatic cancer in male smokers (Finland). Cancer Epidemiol Biomarkers Prev 17:553–562

Boccardo F, Lunardi G, Guglielmini P, Parodi M, Murialdo R, Schettini G, Rubagotti A (2004) Serum enterolactone levels and the risk of breast cancer in women with palpable cysts. Eur J Cancer 40(1):84–89

Bode AM, Dong Z (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4:793–805

Bosetti C, Rossi M, McLaughlin JK, Negri E, Talamini R, Lagiou P, Montella M, Ramazzotti V, Franceshi S, LaVecchia C (2007)

Brand W, Schutte ME, Williamson G, van Zanden JJ, Cnubben NH, Groten JP, van Bladeren PJ, Rietjens IM (2006) Flavonoidmediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed Pharmacother 60:508–519

Bravo L (1988) Polyphenols: Chemistry, dietary sources,metabolism, and nutritional significance. Nutr Rev 56: 317–333.

Bridges AJ (2001) Chemical inhibitors of protein kinases. Chem Rev 101:2541–2572

Brown AK, Papaemmanouil A, Bhowruth V, Bhatt A, Dover LG, Besra GS (2007) Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II. Microbiology 153:3314–3322

Brueggemeier RW, Gu X, Mobley JA, Joomprabutra S, Bhat AS, Whetstone JL (2001) Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism. Ann N Y Acad Sci 948:51–66

Caltagirone S, Rossi C, Poggi A, Ranalletti FO, Natali PG, Brunetti M, Aiello FB, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600

Carr AM (2000) Cell cycle: piecing together the p53 puzzle. Science 287:1765–1766

Casagrande F, Darbon JM (2001) Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem Pharmacol 61:1205–1215

Cermak R (2008) Effect of dietary flavonoids on pathways involved in drug metabolism. Expert Opin Drug Metab Toxicol 4:17–35

Cermak R, Landgraf S, Wolffram S (2004) Quercetin glucosides inhibit glucose uptake into brush-border-membrane vesicles of porcine jejunum. Br J Nutr 91:849–855

Chahar MK, Sharma N, Dobhal MP, Joshi YC (2011) Flavonoids: a versatile source of anticancer drugs. Phcog Rev 5:1–12

Cheng HL, Hsu PY, Chow NH (2005) The novel targets for antiangiogenesis of genistein on human cells. Biochem Pharmacol 69:307–318

Chiu FL, Lin JK (2008) Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and

Ciolino HP, Daschner PJ, Yeh GC (1999) Dietary flavonoids quercetin and kaempferol are ligands of aryl hydrocarbon receptor that affect CYP1A1 differentially. Biochem J 340:715–722

Clifford AH, Cuppett SL (2000) Review: Anthocyanins—nature, occurrence and dietary burden. J Sci Food Agric 80: 1063–1072.

Clifford MN (2004) Diet-derived phenols in plasma and tissues and their implications for health. Planta Med 12:1103–1114

Clifford MN, Brown JE (2006) Dietary flavonoids and health— broadening the perspective. In: Andersen ØM, Markham KR (eds) Flavonoids: chemistry, biochemistry and application,

Conseil G, Baubichon-Cortay H, Dayan G, Jault JM, Barron D (1998) Flavonoids: a class of modulators with bifunctional interactions at ATP- and steroid-binding sites on mouse P-glycoprotein. Proc Natl Acad Sci USA 95:9831–9836

Cook NC, Samman S (1996) Review: Flavonoids chemistry,metabolism,cardioprotectiveeffects, and dietary sources. J NutrBiochem 7: 66–76.

Cotroneo MS, Wang J, Fritz WA, Eltoum IE, Lamartiniere CA (2002) Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis 23:1467–1474

D’Alessandro T, Prasain J, Botting NP, Moore R, Darley-Usmar VM, Patel RP, Barnes S (2003) Polyphenols, inflammatory response, and cancer prevention: chlorination of isoflavones by human neutrophils. J Nutr 133:3773S–3777S

Dai Q, Franke AA, Jin F, Shu XO, Hebert JR, Custer LJ, Cheng J, Gao YT, Zheng W (2002) Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai. Cancer Epidemiol Biomarkers Prev 11:815–821

Dalu A, Haskell JF, Coward L, Lamartiniere CA (1998) Genistein, a component of soy, inhibits the expression of the EGF and ErbB/ Neu receptors in the rat dorsolateral prostate. Prostate 37:36–43

Dangles O, Dufour C (2005) Flavonoids–protein interactions. In: Andersen ØM, Markham KR (eds) Flavonoids chemistry, biochemistry and applications. CRC Press, pp 443–469

Das DK (1994) Naturally occurring flavonoids: structure, chemistry, and high performance liquid chromatography methods for separation and characterization. Methods Enzymol 234:410–420

De Santi C, Pietrabissa A, Mosca F, Rane A, Pacifici GM (2002) Inhibition of phenol sulfotransferase (SULT1A1) by quercetin in human adult and foetal livers. Xenobiotica 32:363–368.

Den Tonkelaar I, Keinan-Boker L, Veer PV, Arts CJ, Adlercreutz H, Thijssen JH, Peeters PH (2001) Urinary phytoestrogens and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev 10(3):223–228

Dhar DN (1994) The chemistry of chalcones and related compounds. Wiley, New York DiPietro A, Conseil G, Perez-Victoria JM, Dayan G, Baubichon- Cortaya H, Trompiera D, Steinfels E, Jault JM, de Wet H, Maitrejan M, Comte G, Boumendjel A, Mariotte AM, Dumontet C, McIntosh DB, Goffeau A, Castanys S, Gamarro F, Barron D (2002) Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol Life Sci 59:307–322

Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O (2001) Effect of soy isoflavone supplementation on markers of oxidative stress in men and women. Cancer Lett 172:1–6

Doostdar H, Burke MD, Mayer RT (2000) Bioflavonoids: selective substrates and inhibitors for cytochromes P450 CYP1A and CYP1B1. Toxicology 144:31–38

Epidemiol Biomarkers Prev 16:1621–1625

Fang SC, Hsu CL, Lin HT, Yen GC (2010) Anticancer effects of flavonoid derivatives isolated from Millettia reticulata Benth in SK-Hep-1 human hepatocellular carcinoma cells. J Agric Food Chem 58(2):814–820

Favot L, Martin S, Keravis T, Andriantsitohaina R, Lugnier C (2003) Involvement of cyclin-dependent pathway in the inhibitory effect of delphinidin on angiogenesis. Cardiovasc Res

Ferguson PJ, Kurowska E, Freeman DJ, Chambers AF, Koropatnic DJ (2004) A flavonoid fraction from cranberrry extract inhibits proliferation of human tumor cell lines. J Nutr 134(6):1529–1535

Ferreira JFS, Luthria DL, Sasaki T, Heyerick A (2010) Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artimisin against malaria and cancer. Molecules  15:3135–3170

Firestone GL, Sundar SN (2009) Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 11:1–15

Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 16(1):98–101

Foti P, Erba D, Riso P, Spadafranca A, Criscuoli F, Testolin G (2005) Comparison between daidzein and genistein antioxidant activity in primary and cancer lymphocytes. Arch Biochem Biophys 433:427–431

Fotsis T, Pepper M, Adlercreutz H, Fleischmann G, Hase T, Montesano R, Schweigerer L (1993) Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 90:2690–2694

Fotsis T, Pepper M, AdlercreutzH,Hase T,Montesano R, Schweigerer L (1995) Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125:790S–797S

Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wa¨ha¨la¨ K, Montesano R, Schweigerer L (1997) Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro

Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP (2004) The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ 329:1447–1450

Fukuyama M, Rokutan K, Sano T, Miyake H, Shimada M, Tashiro S (2005) Overexpression of a novel superoxide producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon. Cancer Lett 221(1):97–104

Galijatovic A, Otake Y, Walle UK, Walle T (2001) Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in Caco-2 cells: potential role in carcinogen bioinactivation. Pharm Res 18:374–379

Gamet-Payrastre L, Manenti S, Gratacap MP, Tulliez J, Chap H, Payrastre B (1999) Flavonoids and the inhibition of PKC and PI 3-kinase. Gen Pharmacol 32:279–286

Garcia-Closas R, Gonzalez CA, Agudo A, Riboli E (1999) Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control 10:71–75

Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E, Bertoncelli L, Cooper EL, Cossarizza A (2011) Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med 2011:591356

Giuliani C, Noguchi Y, Harii N, Napolitano G, Tatone D, Bucci I, Piantelli M, Monaco F, Kohn LD (2008) The flavonoid quercetin regulates growth and gene expression in rat FRTL-5 thyroid cells. Endocrinology 149(1):84–92

Goetzl MA, VanVeldhuizen PJ, Thrasher JB (2007) Effect of soy phytoestrogens on the prostate. Prostate Cancer Prostatic Dis 10:216–223

Gould KS, Lister C (2005) Flavonoid functions in plants. In: Andersen OM, Markham KR (eds) Flavonoids chemistry, biochemistry and applications. CRC Press Taylor & Francis

Grange JM, Davey RW. Antibacterial properties of propolis (beeglue). J R Soc Med 1990;83:159–60.

Griffiths LA, Barrow A (1972) The fate of orally and parenterally administered flavonoids in the mammal. The significance of biliary excretion. Angiologica 9:30–42

Group, London, pp 397–442

Guo JY, Li X, Browning JD Jr, Rottinghaus GE, Lubahn DB, Constantinou A, Bennink M, MacDonald RS (2004) Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer. J Nutr

Hackett AM (1986) The metabolism of flavonoid compounds in mammals. In: Cody V, Middleton E Jr, Harborne JB (eds) Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure–activity relationships. Alan R Liss lnc, New

Haddad AQ (2008) The cellular and molecular properties of flavonoids in prostate cancer chemoprevention. Ph.D Thesis, Institute of Medical Science, University of Toronto

Harborne JB (ed) (1994) The flavonoids: advances in research since 1986. Chapman & Hall, London Harborne JB, Williams CA (2000) Advances in flavonoid research since 1992. Phytochemistry 55(6):481–504

Harborne JB, Baxter H. The handbook of natural flavonoids, Vols 1 and 2. Chichester, UK: John Wiley and Sons; 1999.

Harborne JB, Mabry TJ, Mabry H. The Flavonoids, London, Chapman and Hall; 1974.

Harborne JB, Turner BL (1984) Plant Chemosystematics. London:Academic Press.

Harborne JB, Williams CA. Advances in flavonoid research since1992. Phytochemistry 2000;55:481–504.

Haslam E (1996) Natural polyphenols (vegetable tannins) as drugs: possible modes of action. J Nat Prod 59:205–215

Hassan S, Mathesius U (2012) The role of flavonoids in root– rhizosphere signalling: opportunities and challenges for improving plant–microbe interactions. J Exp Bot 63(9):3429–3444

Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H (2003) Role of p53 and NF-kappaB in epigallocatechin-3- gallateinduced apoptosis of LNCaP cells. Oncogene 22:4851–4859

Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol 1983;32:1141-8.

Havsteen BH (2002) The biochemistry and medical significance of flavonoids. Pharmacol Ther 96:67–202

He L, Wu Y, Lin L, Wang J, Wu Y, Chen Y, Yi Z, Liu M, Pang X (2011) Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by

Heinonen M, Rein D, Teresa Satue´-Gracia M, Huang S-W, Bruce- German J, Frankel EN (1998) Effect of protein on the antioxidant activity of phenolic compounds in a lecithin–

Heller W, Forkmann G (1993) Biosynthesis. In: Harborne JB (ed) The flavonoids. Advances in research since 1986. Chapman and Hall Ltd, London, pp 499–535

Hertog MGL, Hollman PCH, Katan MB (1992) Content of potentially anticinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J Agric Food Chem 40:2379–2383

Hertog MGL, Hollman PCH, Katan MB, Kromhout D (1993b) Intake of potentially anticarcinogenic flavonoids and their determinants in adults in the Netherlands. Nutr Cancer 20:21–29

Hertog MGL, Hollman PCH, van de Putte B (1993a) Content of

Ho CT, Osawa T, Huang MT, Rosen RT (1994) Food Phytochemicals for Cancer Prevention. II. Teas, Spices, and Herbs. Austin, TX:American Chemical Society.

Ho JS, Ma W, Mao DY, Benchimol S (2005) p53-dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Mol Cell Biol 25:7423–7431

Hodek P, Tepla M, Krizkova J, Sulc M, Stiborova M (2009) Modulation of cytochrome P450 enzyme system by selected flavonoids. Neuro Endocrinol Lett 30(1):67–71

Hodek P, Trefil P, Stiborova M (2002) Flavonoids: potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 139(1):1–21

Holland B, Welch AA, Unwin ID, Buss DH, Paul AA, Southgate DAT (1995) McCance and Widdowson’s the composition of foods, 5th edn. Royal Society of Chemistry, Cambridge

Hollman PCH (2004) Absorption, bioavailability, and metabolism of flavonoids. Pharm Biol 42(S):74–83

Hollman PCH, Katan MB (1998) Absorption, metabolism, and bioavailability of flavonoids. In: Rice-Evans CA, Paker L (eds) Flavonoids in health and disease. Marcel Dekker Inc, New York, pp 483–522

Hollman PCH, Katan MB (1999) Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol 37:937

Holzbeierlein JM, McIntosh J, Thrasher JB (2005) The role of soy phytoestrogens in prostate cancer. Curr Opin Urol 15:17–22

Huang MT, Osawa T, Ho CT, Rosen RT (1994) Food Phytochemicals for Cancer Prevention. I. Fruits and Vegetables. Austin, TX:American Chemical Society.

in human jejunum in vivo. Drug Metab Dispos 31:805–813

Ingram D, Sanders K, Kolybaba M, Lopez D (1997) Case control study of phyto-oestrogens and breast cancer. Lancet 350:990–994

Johnson DW, Berg JN, Baldwin MA et al (1996) Mutations in the activin receptor-like kinase I gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189–195

Johnson IT (2004) New approaches to the role of diet in the prevention of cancers of the alimentary tract. Mutat Res 551(1–2):9–28

Johnson J, Maher P, Hanneken A (2009) The flavonoid, eriodictyol, induces long-term protection in ARPE-19 cells through its effects on Nrf2 activation and phase II gene expression. Invest Ophthalmol Vis Sci 50(5):2398–2406

Joussen AM, Rohrschneider K, Reichling J, Kirchhof B, Kruse FE (2000) Treatment of corneal neovascularization with dietary isoflavonoids and flavonoids. Exp Eye Res 71(5):483–487

Ju W, Wang X, Shi H, Chen W, Belinsky SA, Lin Y (2007) A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor kappa B pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol 71:1381–1388

Kameshwaran S, Suresh V, Arunachalam G, Kanthlal SK, Mohanraj M (2012) In vitro and in vivo anticancer activity of methanolic flower extract of Tecoma stans flower. Int Res J Pharm 3(3): 246–252

Kang ZC, Tsai SJ, Lee H (1999) Quercetin inhibits benzo[a]pyreneinduced DNA adducts in human Hep G2 cells by altering cytochrome P-450 1A1 expression. Nutr Cancer 35:175–179

Kilkkinen A, Virtamo J, Vartiainen E, Sankila R, Virtanen MJ, Adlercreutz H, Pietinen P (2004) Serum enterolactone concentration is not associated with breast cancer risk in a nested case– control study. Int J Cancer 108(2):277–280

Kim H, Peterson TG, Barnes S (1998) Mechanisms of action of the soy isoflavone genistein: emerging role of its effects through transforming growth factor beta signaling pathways. Am J Clin Nutr 68:1418S–1425S

Kim JH, Kang JW, Kim MS, Bak Y, Park YS, Jung KY, Lim YH, Yoon DY (2012) The apoptotic effects of the flavonoid N101-2 in human cervical cancer cells. Toxicol In Vitro 26(1):67–73

Kim MH (2003) Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. J Cell Biochem 89(3):529–538

Kim YJ et al (2004) Superoxide anion scavenging and xanthine oxidase inhibition of (þ)-catechin—aldehyde polycondensates. Amplification of the antioxidant property of (þ)-catechin by polycondensation with aldehydes. Biomacromolecules 5:547

Kioka M, Hosokawa N, Komano T, Hirayoshi K, Nagata K, Ueda K (1992) Quercetin, a bioflavonoid, inhibits the increase of human multidrug resistance gene (MDR1) expression caused by arsenite. FEBS Lett 301:307–309

Knekt P, Jarvinen R, Reunanen A, Maatela J (1996) Flavonoid intake and coronary mortality in Finland: a cohort study. Br Med J 312:478–481

Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliovaara M, Reunanen A, Hakulinen T, Aromaa A (2002) Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 76:560–568

Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C, Williamson G (2004) How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr

Kruse FE, Joussen AM, Fotsis T et al (1997) Inhibition of neovacularization of the eye by dietary factors exemplified by isoflavonoids. Ophthalmologie 94:152–156

Kuiper GGJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors a and b. Endocrinology 138:863–870

Kuiper GGJM, Lemmen JG, Carlsson BO, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor b. Endocrinology 139:4252–4263

Kumar PS, Sucheta S, Deepa VS, Selavamani P, Latha S (2008) Antioxidant activity in some selected Indian medicinal plants. African J Biotechnol 7(12):1826–1828

Kurisawa M, Chung JE, Kim YJ, Uyama H, Kobayashi S (2003) Amplification of antioxidant activity and xanthine oxidase inhibition of catechin by enzymatic polymerization. Biomacromolecules 4:469–471

Lagiou P, Rossi M, Lagiou A, Tzonou A, La Vecchia C, Trichopoulos D (2008) Flavonoid intake and liver cancer: a case–control study in Greece. Cancer Causes Control 19(8):813–818

Lai H, Sasaki T, Singh NP, Messay A (2005) Effects of artemisinintagged holotrasferrin on cancer cells. Life Sci 76:1267–1279

Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto CH, Helenowski I, Pelling JC, Bergan RC (2008) Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 68:2024–2032

Le Bail JC, Laroche T, Marre-Fournier F, Habrioux G (1998) Aromatase and 17b-hydroxysteroid dehydrogenase inhibition by flavonoids. Cancer Lett 133:101–110

Le Marchand L, Murphy SP, Hankin JH, Wilkens LR, Kolonel LN

Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H, Tian B (2011a) Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol 108(2):84–93

Li X, Wang JN, Huang JM, Xiong XK, Chen MF, Ong CN, Shen HM, Yang XF (2011b) Chrysin promotes tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced apoptosis in human cancer cell lines. Toxicol In Vitro 25(3):630–635.

Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, Sarkar FH (2006) Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/ receptor activator of nuclear factor-B (RANK)/RANK ligand/ MMP-9 signaling in prostate cancer. Cancer Res 66:4816–4825

Li YC (2011) Antioxidant activity of flavonoids from sweet potato vines in vitro. Adv Mater Res 236–238:2634–2638

Lim SD, Sun C, Lambeth JD, Marshall F, Amin M, Chung L, Petros JA, Arnold RS (2005) Increased Nox1 and hydrogen peroxide in prostate cancer. Prostate 62(2):200–207

liposome oxidation system. J Agric Food Chem 46:917–922

Liu EH, Qi LW, Li P (2010) Structural relationship and binding mechanisms of five flavonoids with bovine serum albumin. Molecules 15:9092–9103

Liu G, Ding L, Luo C, Yang H, Yang D, Liang G, Wang L (2006) Protection against DNA damage and inhibition of lipid peroxidation by flavones from Eremosparton songoricum (Litv) Vass. Res Chem Intermed 32(2):145–152

Liu PX, Gao J, Chen YJ, Long W, Shen X, Tang WS (2011) Anticancer activity of total flavonoids isolated from Xianhe Yanling Recipe. Chin J Integr Med 17(6):459–463

Liu SL, Lin X, Shi DY, Cheng J, Wu C, Zhang YD (2002) Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways. Arch Biochem Biophys 406:173–182

Lund TD, Munson DJ, Haldy ME, Setchell KDR, Lephart ED, Handa RJ (2004) Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod 70:1188–1195

Luo H, Daddysman MK, Rankin GO, Jiang BH, Chen YC (2010) Kaempferol enhances cisplatin’s effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc. Cancer Cell Int 10:16

Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C (1997) Bioavailability of rutin and quercetin in rats. FEBS Lett 409:12–16

Marchetti F, De Santi C, Vietri M, Pietrabissa A, Spisni R, Mosca F, Pacifici GM (2001) Differential inhibition of human liver and duodenum sulphotransferase activities by quercetin, a flavonoid present in vegetables, fruit and wine. Xenobiotica 31:841–847

McCann SE, Moysich KB, Freudenheim JL, Ambrosone CB, Shields PG (2002) The risk of breast cancer associated with dietary lignans differs by CYP17 genotype in women. J Nutr

McCann SE, Muti P, Vito D, Edge SB, Trevisan M, Freudenheim JL (2004) Dietary lignan intakes and risk of pre- and postmenopausal breast cancer. Int J Cancer 111(3):440–443

McRae JM, Kennedy JA (2011) Wine and grape tannin interactions with salivary proteins and their impact on astringency: a review of current research. Molecules 16:2348–2364

Meng X, Lee MJ, Li C, Sheng S, Zhu N, Sang S, Ho CT, Yang CS (2001) Formation and identification of 40-O-methyl-(-)-epigallocatechin in humans. Drug Metab Dispos 29:789–793

Messina MJ, Persky V, Setchell KDR, Barnes S (1994) Soy intake and cancer risk; a review of the in vitro and in vivo data. Nutr Cancer 21:114–131

Middleton E, Kandaswami C (1994) The impact of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In: Harborne JB (ed) The flavonoids, advances in research since 1986. Chapman & Hall, London, pp 619–645 Mitchell JH, Gardner PT, Mcphail DB, Morrice PC, Collins AR, Duthie GG (1998) Antioxidant efficacy of phytoestrogens in chemical and biological model systems. Arch Biochem Biophys

Middleton Jr E, Chithan K. The impact of plant flavonoids on mammalianbiology: implications for immunity, inflammation and cancer.In: Harborne JB, editor. The flavonoids: advances in researchsince 1986. London, UK: Chapman and Hall; 1993.

Modak B, Torres R, Urzu´a A (2011) Seasonal variation of the flavonoids pinocembrin and 3-O-methylgalangin, in the surface component mixture (resinous exudates and waxy coating) of Heliotropium stenophyllum. J Chil Chem Soc 56(1):532–534

Molepo RS (2010) Flavonoid induction of cytochrome P450 (CYP) in human esophageal carcinoma cells: implications for chemotherapy. M. Sc Thesis, University of the Witwatersrand, Johannesberg Monasterio A, Urdaci MC, Pinchuk IV et al. (2004) Flavonoids induce apoptosis in human leukemia U937 cells through caspaseand caspase calpaindependent pathways. Nutr cancer 50:90–100

Moon YJ, Wang X, Morris ME (2006) Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 20(2): 187–210

Morris ME, Zhang S (2006) Flavonoid–drug interactions: effects of flavonoids on ABC transporters. Life Sci 78:2116–2130

Mueller SO, Simon S, Chae K, Metzler M, Korach KS (2004) Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor (alpha) and ER(beta) in human cells. Toxicol Sci 81:530–531

Nakase I, Gallis B, Takatani-Nakase T, Oh S, Lacoste E, Singh NP, Goodlett DR, Tanaka S, Futaki S, Lai H, Sasaki T (2009) Transferrin receptor-dependent cytotoxicity of artemisinin–

Nardini M, Cirillo E, Natella F, Scaccini C (2002) Absorption of phenolic acids in humans after coffee consumption. J Agric Food Chem 50:5735–5741

Nat Cell Biol 4:E131–E136 Sivonˇova´ M, Z ˇ itnˇanova´ I, Hora´kova´ L, S ˇ trosova´ M, Muchova´ J, Balgavy´ P, Dobrota D, D ˇ uracˇkova´ Z (2006) The combined effect of pycnogenol with ascorbic acid and trolox on the oxidation of lipids and proteins. Gen Physiol Biophys 25:379–396

Neuhouser ML (2004) Dietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer 50(1):1–7

Nijeveldt R, Nood EV, Hoorn DECV, Boelens PG, Norren KV, Leeawen PAMV (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin

Nothlings U, Murphy SP, Wilkens LR, Boeing H et al (2008) A food pattern that is predictive of flavonol intake and risk of pancreatic cancer. Am J Clin Nutr 88(6):1653–1662

Nutr 74:418–425

Ofer M, Wolffram S, Koggel A, Spahn-Langguth H, Langguth P (2006) Modulation of drug transport by selected flavonoids: involvement of P-gp and OCT? Eur J Pharm Sci 25(2–3):263–271

Ogbuewu IP, Uchegbu MC, Emenalom OO, Okoli IC, Iloeje MU (2010) Overview of the chemistry of soy isoflavones, potential threats and potential therapeutic benefits. Electron J Environ Agric Food Chem 9(4):682–695

Oh S, Kim BJ, Singh NP, Lai H, Sasaki T (2009) Synthesis and anticancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett 274:33–39

Ohta T, Nakatsugi S, Watanabe K, Kawamori T, Ishikawa F, Morotomi M, Sugie S, Toda T, Sugimura T, Wakabayashi K (2000) Inhibitory effects of bifido-bacterium-fermented soy milk on PhIP-induced rat mammary carcinogenesis, with partial contribution of its component isoflavaones. Carcinogenesis 21:937–941

Oikawa T, Shimamura M, Ashino H, Nakamura O, Kanayasu T, Morita I, Murota S (1992) Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor. J Antibiot (Tokyo) 45:1155–1160

Okushio K, Matsumoto N, Kohri T, Suzuki M, Nanjo F, Hara Y (1996) Absorption of tea catechins into rat portal vein. Biol Pharm Bull 19:326–329

Olthof MR, Hollman PC, Buijsman MN, van Amelsvoort JM, Katan MB (2003) Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans. J Nutr 133:1806–1814

Olthof MR, Hollman PC, Vree TB, Katan MB (2000) Bioavailabilities of quercetin-3-glucoside and quercetin-40-glucoside do not differ in humans. J Nutr 130:1200–1203

Ørgaard A, Jensen L (2008) The effects of soy isoflavones on obesity. Exp Biol Med 233(9):1066–1080

Orsˇolic´ N, Benkovic´ V, Lisicˇic´ D, Ðikic´ D, Erhardt J, Knezˇevic´ AH (2010) Protective effects of propolis and related polyphenolic/ flavonoid compounds against toxicity induced by irinotecan.  Med Oncol 27(4):1346–1358

Parr AJ, Bolwell GP (2000) Phenols in the plant and in man. The potential for possible nutritional enhancement of the diet by modifying phenolic content or composition. J Sci Food Agric  80:985–1012.

Pascual-Teresa D, Santos-Buelga S, Rivas-Gonzalo JC (2000) Quantitative analysis of flavan-3-ols in Spanish foodstuffs and beverages. J Agric Food Chem 48:5331–5337

Passamonti S, Terdoslavich M, Franca R, Vanzo A, Tramer F, Braidot E, Petrussa E, Vianello A (2009) Bioavailability of flavonoids: a review of their membrane transport and the function of bilitranslocase in animal and plant organisms. Curr Drug Metab 10:369–394

Patel MJ (2008) A review of potential health benefits of flavonoids. Lethbridge Undergrad Res J 3(2) Peng W, Kuo SM (2003) Flavonoid structure affects the inhibition of lipid peroxidation in caco-2 intestinal cells at physiological concentrations. J Nutr 133(7):2184–2187

Peng Y, Li QW, Jian L (2011) Antitumor activity of Scutellaria baicalensis Georgi total flavonoids on mice bearing U14 cervical carcinoma. Afr J Biotechnol 10(82):19167–19175

Perez JL, Jayaprakasha GK, Cadena A, Martinez E, Hassan A, Patil BS (2010) In vivo induction of phase II detoxifying enzymes, glutathione transferase and quinone reductase by citrus triterpenoids. BMC Complement Altern Med 10:51

Perez-Victoria JM, Chiquero MJ, Conseil G, Dayan G, Di Pietro A, Barron D, Castanys S, Gamarro F (1999) Correlation between the affinity of flavonoids binding to the cytosolic site of Leishmania tropica multidrug transporter and their efficiency to revert parasite resistance to daunomycin. Biochemistry 38:1736–1743

Perez-Vizcaino F, Duarte J, Jimenez R, Santos-Buelga C, Osuna A (2009) Antihypertensive effects of the flavonoid quercetin. Pharmacol Rep 61(1):67–75

Peterson J, Lagiou P, Samoli E, Lagiou A, Katsouyanni K et al (2003) Flavonoid intake and breast cancer risk: a case control study in Greece. Br J Cancer 89(7):1255–1259

Petri N, Tannergren C, Holst B, Mellon FA, Bao Y, Plumb GW, Bacon J, O’Leary KA, Kroon PA, Knutson L, Forsell P, Eriksson T, Lennernas H, Williamson G (2003) Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes,

Phan TA, Yu XM, Kunnimalaiyaan M, Chen H (2011) Antiproliferative  effect of chrysin on anaplastic thyroid cancer. J Surg Res 170(1):84–88

Pharmacol 56:1039–1044

Pietinen P, Stumpf K, Ma¨nnisto¨ S, Kataja V, Uusitupa M, Adlercreutz H (2001) Serum enterolactone and risk of breast cancer: a case– control study in Eastern Finland. Cancer Epidemiol Biomarkers Prev 10:33

 Pike ACW, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, Ljunggren J, Gustafsson JA° , Carlquist M (1999) Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 18:4608–4618

Poli G, Leonarduzzi G, Biasi F, Chiarpotto E (2004) Oxidative stress and cell signalling. Curr Med Chem 11(9):1163–1182

Qin Y, Li Z, Chen Y, Hui H, Sun Y, Yang H, Lu Na, Guo Q (2012) III-10, a newly synthesized flavonoid, induced differentiation of human U937 leukemia cells via PKCd activation. Eur J Pharm Sci 45(5):648–656

Rahman S, Salehin F, Iqbal A (2011) In vitro antioxidant and anticancer activity of young Zingiber officinale against human breast carcinoma cell lines. BMC Complement Altern Med 11:76

Ravichandiran V, Ahamed HN, Nirmala S (2011) Natural flavonoids and lung cancer. Pharmacie Globale 6(2):1–9

Ren W, Qiao Z, Wang H, Zhu L and Zhang L, Flavonoids: promising anticancer agents, Med Res Rev, 2003, 23(4), 519-534.

Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523–1526

Robards K, Antolovich M (1997) Analytical chemistry of fruit bioflavonoids. Analyst 122:11R–34R

Rodriguez-Proteau R, Mata JE, Miranda CL, Fan Y, Brown JJ, Buhler DR (2006) Plant polyphenols and multidrug resistance: effects of dietary flavonoids on drug transporters in Caco-2 and MDCKIIMDR1 cell transport models. Xenobiotica 36(1):41–58

Romanouskaya TV, Grinev VV (2009) Cytotoxic effect of flavonoids on leukemia cells and normal cells of human blood. Bull Exp Biol Med 148(1):57–59

Rossi M, Bosetti C, Negri E, Lagiou P, La Vecchia C (2010) Flavonoids, proanthocyanidins, and cancer risk: a network of case–control studies from Italy. Nutr Cancer 62(7):871–877

Rossi M, Garavello W, Talamini R, Negri E, Bosetti C, Dal Maso L, Lagiou P, Tavani A, Polesel J, Barzan L, Ramazzotti V, Franceschi S, Vecchia C (2007) Flavonoids and the risk of oral and pharyngeal cancer: a case–control study from Italy. Cancer

Roy AM, Baliga MS, Katiyar SK (2005) Epigallocatechin-3-gallate induces apoptosis in estrogen receptor-negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation. Mol Cancer Ther 4:81–90

Rudrabhatla P, Rajasekharan R (2005) Functional characterization of peanut serine/threonine/tyrosine protein kinase: molecular docking and inhibition kinetics with tyrosine kinase inhibitors.  Biochemistry 43(38):12123–12132

Ruela-de-Sousa RR, Fuhler GM, Blom N, Ferreira CV, Aoyama H, Peppelenbosch MP (2010) Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death Dis 1(1):19

Russo GL (2007) Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem Pharmacol 74(4):533–544

Saewan N, Koysomboon S, Chantrapromma K (2011) Anti-tyrosinase and anti-cancer activities of flavonoids from Blumea balsamifera DC. J Med Plants Res 5(6):1018–1025

Samanta A, Das G, Das SK (2011) Roles of flavonoids in plants. Int J Pharm Sci Technol 6(1):12–35

Sandhar HK, Kumar B, Prasher S, Tiwari P, Salhan M, Sharma P (2011) A review of phytochemistry and pharmacology of flavonoids. Int Pharm Sci 1:25–41

Sathyamoorthy N, Gilsdorf JS, Wang TT (2005) Differential effect of genistein on transforming growth factor beta1 expression in normal and malignant mammary epithelial cells. Anticancer Res 18(4A):2449–2453

Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y, Yano M, Ito A (2002) Inhibition of activator protein-1 binding activity and phosphatidylinositol-3-kinase pathway by nobelitin, a polyhydroxy flavonoid, results in augmentation of TIMP-1 production and

Scalbert A, Williamson G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130:S2073–S2085

Scheline RR (1991) Handbook of mammalian metabolism of plant compounds. CRC Press, Boca Raton Schindler R, Mentlein R (2006) Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J Nutr 136(6):1477–1482

Schmidt F, Knobbe CB, Frank B, Wolburg H, Weller M (2008) The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. Oncol Rep 19:1061–1066

Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice- Evans C (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23:861–880

Schroeter H, Spencer JP, Rice-Evans C, Williams RJ (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein- induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J 358:547–557

Seelinger G, Merfort I, Wolfle U, Schempp CM (2008) Anticarcinogenic effects of the flavonoid luteolin. Molecules 13:2628–2651.

Selvendiran K, Koga H, Ueno T, Yoshida T, Maeyama M, Torimura T, Yano H, Kojiro M, Sata M (2006) Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. Cancer Res 66(9):4826–4834

Seufi AM, Ibrahim SS, Elmaghraby TK, Hafez EE (2009) Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 28:80

Shapiro AB, Ling V (1997) Effects of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 53:587–596

Sharma H, Clark C. Contemporary Ayurveda, Edinburgh, Churchill Livingstone; 1998.

Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death.

So FV, Guthrie N, Chambers AF, Carroll KK (1997) Inhibition of proliferation of estrogen receptor positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett 112:127–133

Spencer CM et al (1988) Polyphenol complexation—some thoughts and observations. Phytochemistry 27:2397–2409

Stefani ED, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Carzoglio JC, Ronco A, Olivera L (1999a) Dietary antioxidants and lung cancer risk: a case–control study in Uruguay. Nutr  Cancer 34:100–110

Stefani ED, Ronco A, Mendilaharsu M, Deneo-Pellegrini H (1999b) Diet and risk of cancer of the upper aerodigestive tract-II. Nutr Oral Oncol 35:22–26

Stevens JF, Page JE (2004) Xanthohumol and related prenylflavonoids from hops and beer: to your good health. Phytochemistry

Su SJ, Yeh TM, Chuang WJ, Ho CL, Chang KL, Cheng HL, Liu HS,

Sugatani J, Yamakawa K, Tonda E, Nishitani S, Yoshinari K, Degawa M, Abe I, Noguchi H, Miwa M (2004) The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biochem Pharmacol 67:989–1000

suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells. Cancer Res 62:1025–1029

Tang NP, Zhou B, Wang B, Yu RB, Ma J (2009) Flavonoids intake and risk of lung cancer: a meta-analysis. Jpn J Clin Oncol 39(6):352–359

targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway. Cancer Sci 102(1):219–225

Tosetti F, Ferrari N, De Flora S, Albini A (2002) Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 16(1):2–14

transferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Lett 274:290–298

 Tsao AS, Edward SK, Hong WK (2004) Chemoprevention of cancer. CA Cancer J Clin 54:150–180

Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266(1):37–56

van der Logt EM, Roelofs HM, Nagengast FM, Peters WH (2003) Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens. Carcinogenesis 24:1651–1656

Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N (2007) Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: chemical diversity, impacts on plant biology and human health. Biotechnol J 2(10):1214–1234

Vidya PR, Senthil MR, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S (2010) The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-jB inhibition. Eur J Pharmacol 649(1–3):84–91

Vietri M, Vaglini F, Pietrabissa A, Spisni R, Mosca F, Pacifici GM (2002) Sulfation of R(–)-apomorphine in the human liver and duodenum, and its inhibition by mefenamic acid, salicylic acid and quercetin. Xenobiotica 32:587–594

von Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P, Greenblatt DJ (2004) Inhibition of human cytochromes P450 by components of Ginkgo biloba. J Pharm

Wagner H, Farkas L (1975) Synthesis of flavonoids. In: Harborne JB, Mabry TJ, Mabry H (eds) The flavonoids. Part I. Academic Press, New York, pp 127–213

Walle T, Walle UK, Halushka PV (2001) Carbon dioxide is the major metabolite of quercetin in humans. J Nutr 131:2648–2652

Walle UK, Walle T (2002) Induction of human UDP-glucuronosyltransferase UGT1A1 by flavonoids-structural requirements. Drug Metab Dispos 30:564–569

Wallstrom P, Wirfalt E, Janzon L, Mattisson I, Elmstahl S, Johansson U, Berglund G (2000) Fruit and vegetable consumption in relation to risk factors for cancer: a report from the Malmo Diet and Cancer Study. Public Health Nutr 3:263–271

Wang B, Zhang X (2012) Inhibitory effects of Broccolini leaf flavonoids on human cancer cells. Scanning 34(1):1–5

Wei H, Bowen R, Cai Q, Barnes S, Wang Y (1995) Antioxidant and antipromotional effects of the soybean isoflavone genistein. Exp Biol Med 208(1):124–130

Wei H, Tye L, Bresnick E, Birt DF (1990) Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice. Cancer Res 50:499–502

Wiegand H, Boesch-Saadatmandi C, Regos I, Treutter D, Wolffram S, Rimbach G (2009) Effects of quercetin and catechin on hepatic glutathione-S transferase (GST), NAD(P)H quinone oxidoreductase 1 (NQO1), and antioxidant enzyme activity levels in rats. Nutr Cancer 61:717–722

Williams RJ, Spencer JPE, Rice-Evans C (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36(7):838–849

Wilson RT, Wang J, Chinchilli V, Richie JP, Virtamo J, Moore LE, Albanes D (2009) Fish, vitamin D and flavonoids in relation to renal cell cancer among smokers. Am J Epidemiol 170(6):717–729

Wiseman H, Casey K, Clarke DB, Barnes KA, Bowey E (2002) Isoflavone aglycone and glucoconjugate content of high- and low-soy UK foods used in nutritional studies. J Agric Food  Chem 50:1404–1410

Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313:17–29

Wiseman H, O’Reilly J, Lim P, Garnett AP, Huang WC, Sanders TAB (1998) Antioxidant properties of the isoflavone phytoestrogen functional ingredient in soy products. In: Sadler M, Saltmarsh M (eds) Functional foods, the consumer, the products

Wiseman H, O’Reilly JD, Adlercreutz H, Mallet AI, Bowey EA, Rowland IR, Sanders TAB (2000) Isoflavone phytoestrogens consumed in soy decrease F2-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr 72:395–400

Wu B, Zhang Q, Shen W, Zhu J (2008) Antiproliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line. Mol Cell Biochem 313:125–132

xenografts. Prostate 68:61–71

Xi J, Guo R (2008) Interactions of puerarin with micelles: pKa shifts and thermodynamics. J Solut Chem 37(1):107–118

Xiao CW (2008) Health effects of soy protein and isoflavones in humans. J Nutr 138:1244S–1249S.

Xiao ZP, Peng ZY, Peng MJ, Yan WB, Ouyang YZ, Zhu HL (2011) Flavonoids health benefits and their molecular mechanism. Med Chem 11(2):169–177

Xu WH, Yuan ZL (2009) Inhibition of experimental alkali-induced corneal neovascularization in rabbits by using genistein. Int J Ophthalmol (7)

Yang SF, Yang WE, Chang HR, Chu SC, Hsieh YS (2008) Luteolin induces apoptosis in oral squamous cancer cells. J Dent Res 87:401–406

Yang ZF, Poon RTP, Liu Y, Lau CK et al (2006) High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis. Mol Cancer Ther

Yoshizumi M, Tsuchiya K, Suzaki Y, Kirima K, Kyaw M, Moon JH, Terao J, Tamaki T (2002) Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway. Biochem Biophys Res Commun

Young JF, Nielsen SE, Haraldsdottir J, Daneshvar B, Lauridsen ST, Knuthsen P, Crozier A, Sandstro¨m B, Dragsted LO (1999) Effect of fruit juice intake on urinary quercetin excretion and biomarkers of antioxidative status. Am J Clin Nutr 69:87–94

Zaman MS, Shahryari V, Deng G, Thamminana S, Saini S et al (2012) Up-regulation of microRNA-21 correlates with lower kidney cancer survival. PLoSONE 7(2):e31060

Zeleniuch-Jacquotte A, Adlercreutz H, Shore RE, Koenig KL, Kato I, Arslan AA, Toniolo P (2004) Circulating enterolactone and risk of breast cancer: a prospective study in New York. Br J Cancer 91(1):99–105

Zhang Q, Zhao XH, Wang ZJ (2008) Flavones and flavonols exert cytotoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol 46:2042–2053

Zhou JR, Mukherjee P, Gugger ET et al (1998) Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 58:5231–5238

Zi XL, Grasso AW, Kung HJ, Agarwal R (1998) A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest and

Middleton E Jr and Kandaswami C, The impact of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In: the flavonoids: advances in research since 1986 by JB Harbourne (Ed). Chapman & hall, London, 1993, pp. 619-652.

Harborne, J. B., in: Introduction to Ecological Biochemistry, 2nd Ed.,Academic Press, New York, NY, 1982.

Duthie GG, Duthie SJ, Kyle JAM(2000) Plant polyphenols in cancerand heart disease: Implications as nutritional antioxidants. Nutr ResRev 13: 79–106.

Chu YH, Chang CL, Hsu HF (2000) Flavonoid content of severalvegetables and their antioxidant activity. J Sci Food Agric 80: 561–566.

HertogMGL,Hollman PCH, KatanMB(1992) Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonlyconsumed in the Netherlands. J Agric Food Chem 40: 2379–2383.

Hertog MGL, Hollman PCH, Van de Putte B (1993) Content of potentiallyanticarcinogenic flavonoids of tea infusions, wines and fruitjuices. J Agric Food Chem 41: 1242–1246.

Arts ICW, Van de Putte B, Hollman PCH (2000) Catechin contents of foods commonly consumed in the Netherlands. 1. Fruits, vegetables,staple foods, and processed foods. J Agric FoodChem48:1746–1751.Arts ICW, Van de Putte B, Hollman PCH (2000) Catechincontentsof foods commonly consumed in the Netherlands. 2. Tea, wine, fruitjuices, and chocolate milk. J Agric Food Chem 48:1752–1757.

Tom´as-Barber´an FA, Clifford MN (2000) Review: Flavanones, chalcones and dihydrochalcones—nature, occurrence and dietary burden.J Sci Food Agric 80: 1073–1080.

Mazza, G., Miniati, E., in: Anthocyanins in Fruits, Vegetables andGrains, CRC Press, Boca Raton, FL, 1993.

Pietta, P. G., Simonetti, P., in: Packer, L., Hiramatsu, M., Yoshikawa, T. (Eds), Antioxidant Food Supplements in Human Health, AcademicPress, San Diego 1999, pp. 283 – 308.

Cook NC, S Flavonoids- chemistry, metabolism, cardio protective effects, and dietary sources. Nutr Biochem 1996; 7: 66- 76.

Świgło G, Tyrakowska B. Quality of Commercial Apple Juices Evaluated on the Basis of the Polyphenol Content and the TEAC Antioxidant Activity, J Food Sci 2003; 68(5):1844-1849.

Gryglewski RJ, Korbut R, Robak J. On the mechanism of antithrombotic action of flavonoids. Biochemical Pharmacol 1987; 36: 317-321.

Gyamfi MA, Yonamine M, Aniya Y Free- radical scavenging action of medicinal herbs from Ghana Thonningiasanguineaonexperimentally- induced liver injuries. Gen Pharmacol 1999; 32: 661-667.

Apak R, Guclu K, Demirata B, Ozyurek M,Esin CS,Bektasoglu B,Berker K, Ozyur D. Comparative evaluation of various total antioxidant capacity assays applied to phenolic compounds withthe CUPRAC assay. Molecules. 12, 2007; 1496-547.