Cancer chemoprevention through dietary flavonoids: what’s limiting?
Chinese Journal of Cancer volume 36, Article number: 50 (2017)
Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges.
Dietary flavonoids are the most common polyphenols found in fruits, vegetables, flowers, chocolate, tea, wine, and other plant sources [1,2,3]. With more than 9000 members in this family, flavonoids can be divided into several subfamilies, including flavones, flavanols, isoflavones, flavonols, flavanones, and flavanonols that differ in their ring substituents and extent of saturation [4, 5]. However, all compounds in this family share the basic chemical structure consisting of two benzene rings connected by a 3-carbon bridge, forming a heterocycle (C6-C3-C6)  (Fig. 1). Flavonoids have been reported to have an excellent safety profile (no toxicity at up to 140 g/day), with no known significant adverse effects . The pharmacological effects of flavonoids include antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, antimicrobial, and anticancer [8, 9]. However, there are significant challenges associated with flavonoids related to their isolation, purification, and pharmacokinetic/pharmacodynamic (PK/PD) properties, which have limited their development into efficacious clinical drugs. Here, we discuss the challenges associated with the development of flavonoids for cancer chemoprevention and efforts to surmount these challenges.
Flavonoids in cancer chemoprevention
Increasing evidence from both epidemiological and laboratory studies suggests that the dietary intake of flavonoids reduces the risk of developing certain types of cancers . Several types of flavonoids have been identified as having antiproliferative efficacy in various cancers, including silymarin, genistein, quercetin, daidzein, luteolin, kaempferol, apigenin, and epigallocatechin 3-gallate [11, 12]. These aforementioned compounds have been reported to have anticancer and preventive effects against prostate , colorectal , breast , thyroid , lung , and ovarian  cancers, among others [19,20,21]. Their chemopreventive efficacy is mediated by (1) inhibiting the development of new cancer cells; (2) preventing carcinogens from reaching their activation sites; and (3) decreasing the toxicity of certain compounds by inhibiting their metabolism [22,23,24]. The molecular mechanisms by which flavonoids produce their anticancer and preventive effects include (1) induction of apoptosis [14, 25, 26]; (2) cell cycle arrest at G1 or G2/M phase by inhibiting key cell cycle regulators such as cyclin-dependent kinases (CDKs) [27, 28]; (3) inhibition of metabolizing enzymes (notably cytochromes P450 [CYPs]), which inhibits the activation of numerous carcinogenic compounds ; (4) inhibition of reactive oxygen species formation primarily by activation of phase II metabolizing enzymes [26, 30, 31]; and (5) inhibition of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenesis [32,33,34]. In addition, some flavonoids have been shown to significantly inhibit multidrug resistance, which is responsible for cancer relapse and chemotherapy failure [35, 36]. However, some flavonoids have specific mechanisms of action that are not characteristic of the flavonoid family. For example, the isoflavones genistein and diadzein have been shown to significantly inhibit cancer growth and proliferation [37,38,39]. Due to their structural similarity with estrogen, genistein and diadzein have been reported to have significant preventive efficacy against breast cancer [40, 41]. Another interesting flavonoid is silybin, which has antioxidant and hepatoprotective efficacy [42,43,44]. However, in vitro and in vivo preclinical studies in the last decade indicate that silybin also has antiproliferative efficacy and, as a result, subsequent phase I and II clinical studies have been conducted [45,46,47]. Silybin has a number of pharmacological properties that may explain its anticancer efficacy, such as inhibition of (1) tumor necrosis factor (TNF)-induced activation of nuclear factor kappa B (NF-κB) where it inhibits the phosphorylation and proteolytic degradation of nuclear factor of kappa light polypeptide gene enhancer in B cell inhibitor, alpha (IκBα) to NF-κB (active form) ; (2) tyrosine kinases ; (3) androgen receptors ; and (4) the epithelial-to-mesenchymal transition embryonic pathways [51,52,53,54]. Another flavonoid, quercetin, is a potent antioxidant that is present in natural sources such as berries, onions, apples, and red wine [3, 55]. Quercetin’s anticancer efficacy in colon cancer and neurogliomas results from activating the novel cell death pathway, autophagy (type II programmed cell death), and mitogen-activated protein kinases (MAPK or extracellular signal-related kinase [ERK]) signaling pathways [56,57,58]. Accordingly, several studies on flavonoids support the potential role of flavonoids in both cancer treatment and prevention . Currently, a variety of flavonoid formulations are present in dietary supplements such as milk thistle and red clover extracts . However, none of the above mentioned flavonoids have been approved for clinical use.
Challenges in flavonoids in cancer chemoprevention development
Despite preclinical evidence suggesting that flavonoids have anticancer and preventive efficacy, there are numerous problems that have impeded the development of dietary flavonoids as approved drugs for clinical use. There are challenges associated with demonstrating the effect of flavonoids in reducing the risk of certain cancer, e.g., the cost and time needed for epidemiological studies, the isolation and purification of flavonoids from their natural sources, and PK issues, among others. These challenges are discussed below, and a summary of these issues is also presented in Fig. 2.
Isolation and purification challenges
One of the major challenges in the extraction of flavonoids from their original plant sources resides in the fact that these compounds are present at very low levels (from micrograms to milligrams per kg of plant masses). Indeed, the continuous extraction of these compounds could result in the extinction of the plant source (assuming extraction is faster than replenishing new plants), disrupting whole plant communities [60, 61].
As with other plant products, flavonoids are usually present in plants as a complex with other compounds that produce their effects in concert. In addition, other secondary metabolites, minerals, vitamins, and fibers are also complexed with flavonoids from the same source . Therefore, the sum of the constituents in the plant may be responsible for the observed anticancer efficacy, as opposed to more than one flavonoid alone . This complexation of flavonoids makes it difficult to isolate and identify the exact molecule that is producing specific pharmacological effects. Also, following the identification of the active flavonoid, its subsequent isolation and purification from other compounds, using analytical methods, is a multistage procedure. A combination of several technologies can be used for isolation of specific compounds, including solvent extraction, column chromatography, medium-pressure liquid chromatography, vacuum column chromatography, and preparative high performance liquid chromatography (HPLC) [63, 64]. The application of such procedures is a time-consuming process that can be associated with high costs . Additionally, even with the application of such complex techniques, the yield of extracted compounds is typically very low as several kilograms of the plant produce less than 1 g of the isolated compounds in some cases . An important factor that limits the extraction yield is the complex nature of biosynthetic pathways for flavonoids in plants. These pathways are considered to be one of the most complex biosynthetic pathways and result in variable flavonoid composition at different growth stages of the plant and under different environmental conditions [67, 68]. The variation in flavonoid composition decreases the predictability of flavonoid yields during extraction and results in inconsistent data after each extraction . Another limitation in the extraction of flavonoids is that these compounds are usually labile, subjecting them to a high level of degradation or alteration in their chemical structures and subsequent loss of activity during purification . Therefore, harvesting flavonoids from their plant natural sources, using the current applied methodologies, can be time-consuming, highly expensive, associated with very low yields and wasteful.
The potential therapeutic effects (as chemopreventive compounds) of natural products such as flavonoids can be ascertained to some extent from epidemiological studies, including retrospective meta-analysis , prospective observational studies , and/or prospective interventional studies [73, 74]. The data from epidemiological studies depend on the population of individuals that have ingested the specific compound. Thus, for this review, the population of interest would consist of those individuals that have taken dietary flavonoids to prevent cancer. It is time-consuming to collect the data and have it categorized, analyzed, and associated with the presence or absence of flavonoids. The data is often skewed due to lack of adherence data in the population using specific flavonoids. Also, the length of exposure is very long, where some changes in the amount and type of exposure can occur rapidly in the population, making the conclusions of the study invalid. Another important limitation is that the population is usually exposed to many heterogeneous factors that can significantly affect health outcomes, including the development of cancer. Such factors can result in conflicting data and decrease the certainty of conclusions about the effect of flavonoids in cancer chemoprevention. For example, the data from epidemiological studies that were used to determine the correlation between the intake of dietary flavonoids and the risk of developing colorectal cancer (CRC) were controversial and inconsistent [75, 76]. Some studies suggested that flavonoid consumption was significantly correlated with a low CRC risk [77,78,79], whereas other studies did not report a significant correlation between the intake of flavonoids and CRC risk [80,81,82]. Therefore, the type of dietary flavonoid that is ingested, the size and heterogeneity of population, and the design of the study can affect the interpretation of results from studies assessing the effectiveness of flavonoids in preventing cancer. The validation of the conclusions derived from appropriately designed epidemiological studies requires conducting expensive studies using large populations, which further limits the development of flavonoids as drugs.
Flavonoids typically have an unsuitable PK profile [83, 84] (i.e., absorption, distribution, metabolism, excretion, and toxicity [ADMET]), characterized by low solubility, poor oral absorption, and extensive hepatic metabolism by phase I and II enzymes [85,86,87]. Flavonoids are usually ingested with other foods components, resulting in the complexation or precipitation of flavonoid compounds, thus limiting their absorption and bioavailability [88, 89]. Furthermore, flavonoids can undergo significant metabolism via de-glycosylation prior to their absorption in the small intestine epithelial cells [90, 91]. In vivo, flavonoids are substrates for glucuronidation, sulfation, and O-methylation , resulting in inert, polar complexes that are rapidly excreted in urine . Furthermore, the unabsorbed form can reach the colon and undergo degradation by the intestinal microflora by ring fission [93,94,95], reduction , or hydrolysis . For example, only 20%–30% of an oral dose of quercetin is bioavailable . The incubation of quercetin under normal physiological conditions (Hanks’ Balanced Salt solution, pH 7.4) results in its degradation within 6 h . The anticancer effect of the flavonoid silybin is limited by its extensive metabolism and low oral absorption [100, 101]. Flavan-3-ols have been shown to be completely degraded after 8 h of exposure to simulated intestinal secretions . These aforementioned PK liabilities represent significant barriers for the clinical development of flavonoids, as the required in vivo levels cannot be achieved even with high oral doses [103, 104]. In addition, the ingestion of higher doses of flavonoids for more effective antiproliferative effect may produce proliferative and inflammatory responses [105, 106]. Finally, flavonoids are known to affect the bioavailability and efficacy of many drugs due to their multiple in vivo interactions. For example, certain flavonoids can affect CYPs  and conjugation enzymes , other enzymes (α-amylase  and α-glucosidases ), bovine hemoglobin , multidrug resistance transporters , colonic microflora , and plasma proteins [114, 115].
ATP-binding cassette drug transporter interactions
The ATP-binding cassette (ABC) transporter superfamily consists of important members that mediate not only PK alterations (i.e., ADMET), but also multidrug resistance (MDR) to numerous antineoplastic drugs, including flavonoids, that are substrates for these transporters, resulting in chemotherapeutic failure [116,117,118,119]. Important members include P-glycoprotein (P-gp or multidrug resistance protein family 1 [MDR1]), breast cancer-resistant protein (BCRP or ATP-binding cassette sub-family G member 2 [ABCG2]), and multidrug resistance protein family C member 1 (ABCC1 or multidrug resistance-associated protein 1 [MRP1]) . The transporters are located on the cell membrane with two transmembrane domains that can recognize different compounds and form channels within the membrane to efflux these compounds . The efflux of the compounds requires the hydrolysis of ATP which provides the energy required for efflux of substrates . ABC transporters have a ubiquitous distribution throughout the body, although they are present in high densities in tissues that have a barrier function, such as the gastrointestinal tract, reproductive organs, kidney, liver, and blood–brain barrier . It is well established that ABC transporters play a critical role in regulating drug absorption, distribution, and excretion, which can decrease their bioavailability and thus their efficacy [124, 125].
Several reports investigated the possible interaction of flavonoids with ABC transporters. Flavonoids, such as flavones (e.g., apigenin and chrysin), isoflavones (e.g., biochanin A and genistein), flavonols (kaempferol), and flavanones (naringenin) have been reported to inhibit the efflux function of ABC transporters, such as ATP-binding cassette subfamily B member 1 (ABCB1) and ABCG2 [112, 126, 127]. The inhibition of ABC transporters by certain flavonoids can have advantages and disadvantages. The inhibition of ABC transporters can increase the bioavailability of some poorly available drugs, thereby potentially augmenting the absorption, distribution, bioavailability, and efficacy of certain drugs, including antineoplastics. Such inhibition can be used to overcome multidrug resistance and chemotherapy failure . For example, the isoflavinoids medicarpin and millepurpan significantly induce apoptosis in multidrug-resistant P388 leukemia cells and overcome the resistance mechanisms . Epigallocatechin-3-gallate, at a dose of 10 mg/kg bodyweight by intragastric gavage as a suspension in 0.2% agar, once a day for 10 days, significantly decreased the expression of P-gp, which increased the plasma levels of atorvastatin and verapamil in male Wistar rats, potentiating their pharmacological actions .
However, the inhibition of ABC transporters by specific flavonoids can potentiate the toxicity of certain ABC substrates and elicit unexpected adverse or toxic effects of these substrates such as antimicrobials [130, 131], immunosuppressants , cardiovascular [133,134,135], and chemotherapeutic drugs [136, 137]. A recent report indicated that some flavonoids (e.g., genistein and glyceollin) also interact with other ABC transporters such as ABCC2 (MRP2) . In addition, certain flavonoids are substrates for ABC transporters, thereby limiting their absorption from the gastrointestinal tract, distribution to body tissues and organs, and, ultimately, their bioavailability . Polymorphisms in the ABC transporter genes can directly affect the PK profile of flavonoids. For example, a recent study showed that the ABCB1 C3435T polymorphism significantly altered the bioavailability and plasma levels of silybin. Patients with CC or CT polymorphisms in the ABCB1 gene have twice the plasma levels of silybin compared to patients with the TT polymorphism . Detailed interactions of flavonoids with CYPs are reviewed elsewhere [108, 137].
CYPs play a significant role in the biotransformation of xenobiotic and endogenous compounds . It is well established that CYPs play a crucial role in phase I metabolism, typically bio-transforming molecules to more polar entities and increasing the likelihood they will be substrates for phase II metabolism. Flavonoids have been reported to significantly inhibit the activities of CYPs . This inhibition is mediated by either a reduction in the level of CYPs or direct binding of flavonoids to their active sites . CYP 3A4 is one of the most important CYP isoforms and is involved in the metabolism of many clinically used drugs . Several types of flavonoids, such as quercetin, kaempferol, naringenin, and apigenin have been shown to have inhibitory effects on the activities of CYPs, primarily CYP 3A4 (both in vivo and in vitro) [143, 144]. This inhibition increases the half-lives and the plasma concentrations of many drugs that are substrates for CYPs, which can potentiate their adverse effects and/or toxicity. For example, the adverse effects of certain calcium channel blockers, statins, antihistamines, protease inhibitors, and immunosuppressants can be significantly potentiated by specific flavonoids . In addition to the inhibition of CYP 3A4, flavonoids were reported to inhibit other CYP isoforms, such as CYP subfamily 1 isoforms (CYP 1A1, CYP 1A2, and CYP 1B1), which are significantly involved in carcinogenesis . The two isoflavones, formononetin and biochanin A, significantly inhibit CYP 1A2 in both human and rat liver microsomes in vitro. Formononetin also significantly inhibits CYP 2D6, and biochanin A also inhibits human CYP 2C9 . CYP 1B1 is inhibited by flavone , chrysin , apigenin , genistein , luteolin , quercetein , galangin , myricetin , and many others. CYP 1A1 is irreversibly inhibited by the binding of two flavones (3-flavone propargyl etherE and 7-Hydroxy flavone) . Finally, CYP gene expression was inhibited by the flavonoids, apigenin , tangeretin , diadzein , silybin , and others. Detailed interactions of flavonoids with CYPs are reviewed elsewhere .
Intestinal microflora interactions
Following the oral administration of flavonoids, it is possible that a significant percentage can reach the colon and be subjected to degradation by microflora, as well as enterohepatic circulation, depending on the compound . The colonic microflora is the most abundant and diverse part of the microbiome in humans . These microorganisms have been shown to biotransform certain drugs to metabolites, thereby altering their efficacies and toxicities [159,160,161]. They also act as a protection barrier involved in the defense against pathogens and toxic xenobiotics. The colonic microflora also reduces cholesterol absorption and increases mucus secretion in the gut [162, 163]. The role of the colonic microflora on the absorption, metabolism, and bioavailability of flavonoids remains to be delineated . It has been reported that unabsorbed flavonoids can be biotransformed to small phenolic compounds that have similar effects, but improved bioavailability, compared to the parent compound . In contrast, the colonic microflora can extensively metabolize (via cleaving the heterocycle break) flavonoids via the enzymes glucuronidase and sulphatase, producing metabolites that are primarily inert polar compounds that are rapidly excreted [164, 166,167,168]. Some flavonoids (e.g., apigenin, genistein, naringenin, and kaempferol) are more likely to undergo microflora degradation compared with others, resulting in lower bioavailability . Recent reports indicated that certain flavonoids can inhibit intestinal microflora and their associated fermentation processes . Both bacterial β-glucosidase and α,β-galactosidase were inhibited by ellagitannins and flavan-3-ols from raspberry extracts .
Furthermore, the use of antibiotics should be monitored when using along with flavonoids as they can alter the composition of the gut microflora, which ultimately affects the bioavailability of specific flavonoids . Thus, the huge diversity in the structures of flavonoids, as well as the microbial composition of gastrointestinal tract, can lower the predictability of the types of interactions that occur, as well as the effect of the resultant compounds and their permeability.
Other PK challenges
The poor chemical stability of flavonoids has been shown to adversely affect PK and limit their utility. Several factors, such as oxygen exposure, temperature, light, ultraviolet radiation, and pH, were shown to reduce flavonoid stability and result in its subsequent degradation . Indeed, increased oxidation due to the presence of oxygen significantly alters cranberry flavonoid stability . Temperature is another factor that needs to be optimized upon the extraction, purification, and storage of flavonoids. For example, the highest yield of phenolic flavonoids from the pericarp of litchi fruit extraction was achieved at 45 °C–60 °C, whereas other temperatures resulted in significantly lower yields and substantial degradation of flavonoids . Light exposure can also alter flavonoid biosynthesis and its biological activities. The optimum antioxidant activity of total flavonoids in the plant Halia bara was at a light wavelength of 310 μmol/m2 s1. Other tested wavelengths reduced the biosynthesis and antioxidant activity of the total flavonoids . Additionally, different pH values can result in distinct yields and activities of flavonoids. A pH range of 3–4 produced the highest yield and bioactivity in phenolics from litchi fruit pericarp . The chemical structure itself and the type of substitution on the flavonoid rings can also alter the chemical stability. For example, the degradation of flavonols when exposed to long wavelength ultraviolet A radiation was increased with more ring substitutions .
The interaction of dietary flavonoids with fiber is another issue, which may significantly affect the absorption and bioavailability of flavonoids [178, 179]. Fibers can delay the absorption of flavonoids from the intestine by two major mechanisms. First, dietary fiber forms complexes with flavonoids, trapping flavonoids in their matrix; second, the fiber can significantly enhance gastric fluid viscosity, which restricts the gastric mixing process, thereby further decreasing the absorption of flavonoids [179, 180].
Approaches to surmount flavonoid PK/PD and other barriers
There are a number of approaches that are being investigated to improve and surmount the challenges associated with clinical use of dietary flavonoids (Fig. 2).
Improving purification and isolation yields
As mentioned earlier, the current traditional isolation and purification techniques usually result in low extraction yield of flavonoids that does not justify the high extraction cost. However, optimization of the conditions in these traditional extraction methods may increase the extraction yield of flavonoids. Response surface methodology (RSM) was applied to optimize flavonoid extraction using ethanol from herbal medicines like Citrus aurantium L. var. amara Engl  and Chinese Huangqi . RSM is a mathematical and statistical method for designing experiments . RSM significantly increased the yield of flavonoids from Chinese Huangqi when the extraction parameters were optimized as follows: ethanol concentration, 52.98%; extraction time, 2.12 h; extraction temperature, 62.46 °C; and a liquid–solid ratio of 35.23 . However, such optimization is required for each plant source of flavonoids and can be time-consuming. Therefore, several novel technologies can be applied to reduce the cost and the loss of extracted flavonoids from their natural sources. One of these is the use of high-speed, counter-current chromatography that has been reported to be of lower cost and produce higher yields compared with other technologies . Another technology that has recently emerged is nano-harvesting, where nanoparticles are used to harvest flavonoids from their sources . The nanoparticles enter the plant structures and are released to bind to the targeted compounds and carry them outside the cells without harming the plants. This technique eliminates the use of organic solvents, allows for continuous production of flavonoids, and has opened a new era in natural product extraction methodologies . The ultrasound-assisted extraction method has been purported to increase extraction efficiency and reduce the required time for extraction [181, 186, 187].
As mentioned in the challenges section, the extraction of certain compounds from the plant source can significantly harm plant communities. Therefore, the microbial production of plant natural products, such as flavonoids, at an industrial scale, is currently an attractive alternative approach [61, 188]. This approach has the potential to preserve the environmental resources and use economical stocks associated with less energy use and waste emission. Currently used microorganisms include Escherichia coli [189, 190] and Saccharomyces cerevisiae [191, 192]. The engineering and synthetic biology of microorganisms encourage the return to natural compounds as promising anticancer agents [61, 193].
Overcoming PK challenges
There are a number of approaches or strategies that can be used to surmount factors that lower the bioavailability of flavonoids. For example, the formulation of flavonoids as certain types of glycosides can result in enhanced bioavailability compared with the flavonoid alone or other types of glycosides . These glycosidic derivatives are substrates for certain intestinal epithelial transporters, which would increase their absorption . The administration of quercetin-4′-O-glucoside resulted in a plasma level that was 5 times higher than of quercetin-3-O-rutinoside. Therefore, the conversion of quercetin glycosides into glucosides can be considered an approach to improve flavonoid bioavailability . Another strategy involves adding piperine to the flavonoid formulations. The use of bioenhancers, such as piperine, which is an amide alkaloid from the plants of the Piperaceae family, is another approach . Piperine significantly inhibits the conjugation of various flavonoid compounds such as quecetin  and epigallocatechin-3-gallate  by certain UDP-glucuronosyltransferase phase II enzymes, decreasing their metabolism and increasing bioavailability [197,198,199]. The use of more specific novel ABC transporter blockers such as lapatinib, nilotinib, or specific small interfering RNA is another option, provided that they do not produce intolerable adverse effects, for flavonoids whose bioavailability is limited by certain ABC transporters . In addition, the efficiency of modulators of the intestinal microflora can be considered to improve the flavonoid bioavailability. Such modulation could be achieved by the use of antibiotics or other formulation products that can bypass the gut microbiome .
One of the most important strategies to optimize the PK/PD parameters is the modification of the flavonoid structure to produce novel derivatives. These compounds would contain the basic pharmacophore of the parent compound to retain their desired effects. Methyl- and hyro-sliybin derivatives have been reported to be 10-fold more potent than the parent compound, sylibin [202,203,204,205]. The introduction of hydrophobic functional groups (e.g., ethyl substitution) on the hydroxyl (OH) groups in quercetin significantly enhances its stability by preventing oxidative degradation of the hydroxyl groups . Furthermore, the hydrophobic substitutions increase lipophilicity (quercetin’s clogP = 2, hydrophobic derivatives clogP = 3–12), which increases penetrability through biological membranes (bioavailability was increased from 10.7% for quercetin to 18.8% for one of its derivatives) . It has also been shown that blocking some groups (e.g., C3 hydroxyl and C7 hydroxyl groups) in quercetin by the introduction of the lipophilic moiety pivaloxymethyl (POM) enhances its solubility, decreases its metabolism, enhances stability (half-life increased from 10 h for quercetin to >72 h for its quercetin-POM conjugates at pH 7.4), and increases its effectiveness by preventing chemical and metabolic hydrolysis . An epoxypropoxy flavonoid derivative (MHY336), by inhibiting the enzyme topoisomerase II enzyme, exhibited significant potency against the prostate cancer cell lines LNCaP, PC-3, and DU145 .
An area that has shown significant growth is the development and use of micro- and nanodelivery systems to maximize the bioavailability of flavonoids [209,210,211,212]. One of these approaches involves the use of kinetically stable nanoemulsion technology, where the lipophilic flavonoids can be prepared as emulsions consisting of extremely small particle size (<200 nm). The emulsified flavonoids are released slowly over time, allowing for a higher surface area for absorption, ultimately improving their absorption and bioavailability after oral administration . Another approach is the advanced delivery system with nano-crystal, self-stabilized pickering emulsions that has been reported to increase the delivery of some flavonoids including silybin . Formulating flavonoids as a povidone-mixed, micelle-based microparticle has been shown to significantly enhance their release and PK profile . The encapsulation of the flavonoid quercetin in Zein nanoparticles increases effectiveness in a mouse model of endotoxemia .
Flavonoid complexing with protein has been shown to increase flavonoid stability in vitro [217, 218]. Several studies suggest that this characteristic of flavonoids can be used to enhance their chemical stability [219,220,221]. The overall stability of the grape skin-derived anthocyanine extracts was enhanced when complexed with the proteins α- and β-casein . Furthermore, studies indicate that other milk-derived proteins (e.g., whey proteins and β-lactoglobulin), when used as carriers, also enhance the chemical stability of anthocyanin extracts and allow for their incorporation as food formulations . The complexation of flavonoids with phospholipids has been reported to enhance their bioavailability . The amphiphilic nature of phospholipids helps in enhancing the passage of compounds across the membranes . Indeed, the complexing of the flavonoid quercetin with phospholipid (phosphatidylcholine) to form a quercetin-phospholipid complex significantly improved the PK parameters (maximum serum concentration that a drug achieves and area under the curve) of quercetin in rats compared with quercetin alone .
The preclinical anticancer effect of certain flavonoids suggests that the flavonoids may prevent certain types of cancer. However, the development of flavonoids is limited by their poor extraction yield, complicated extraction methods, the cost and difficulties of epidemiological studies, and their unfavorable PK characteristics. Versatile strategies are being applied to overcome such limitations. Future studies are required to determine whether these strategies can be applied economically and safely. The modulation of phase II metabolism and intestinal microflora can affect the metabolism, bioavailability, and toxicity of other drugs. It also can modulate the availability of dietary minerals and vitamins, thereby having potential impacts on health. Consequently, it may be more preferable to conduct research directed towards new delivery systems, such as nano-emulsions and nanoparticles. These delivery systems should be expected to have enhanced target specificity and safety. However, the cost of developing natural products and applying these strategies should be considered in the light of the cost of currently available synthetic compounds.
Chahar MK, Sharma N, Dobhal MP, et al. Flavonoids: a versatile source of anticancer drugs [J]. Pharmacogn Rev. 2011;5(9):1–12.
Katyal P, Bhardwaj N, Khajuria R. Flavonoids and their therapeutic potential as anticancer agents; biosynthesis, metabolism and regulation [J]. World J Pharm Pharm Sci. 2014;3(6):2188–216.
Harris Z, Donovan MG, Branco GM, Limesand KH, Burd R. Quercetin as an emerging anti-melanoma agent: a four-focus area therapeutic development strategy. Front Nutr. 2016;3:48.
Si HY, Li DP, Wang TM, et al. Improving the anti-tumor effect of genistein with a biocompatible superparamagnetic drug delivery system [J]. J Nanosci Nanotechnol. 2010;10(4):2325–31.
Nema R, Jain P, Khare S, Pradhan A. Flavonoid and cancer prevention—mini review. Res Pharm. 2015;2(2):46–50.
Hodek P, Trefil P, Stiborova M. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes p450 [J]. Chem Biol Interact. 2002;139(1):1–21.
Hertog MGL, Hollman PCH, van de Putte B. Content of potentially anticarcinogenic flavonoids of tea infusions, wines, and fruit juices [J]. J Agric Food Chem. 1993;41(8):1242–6.
Gontijo VS, Dos Santos MH, Viegas C Jr. Biological and chemical aspects of natural biflavonoids from plants: a brief review. Mini Rev Med Chem. 2016. doi:10.2174/1389557517666161104130026.
Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview [J]. Sci World J. 2013;2013:162750.
Neuhouser ML. Dietary flavonoids and cancer risk: evidence from human population studies [J]. Nutr Cancer. 2004;50(1):1–7.
Ohga N, Hida K, Hida Y, et al. Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cells [J]. Cancer Sci. 2009;100(10):1963–70.
Bermudez-Soto MJ, Larrosa M, Garcia-Cantalejo J, et al. Transcriptional changes in human caco-2 colon cancer cells following exposure to a recurrent non-toxic dose of polyphenol-rich chokeberry juice [J]. Genes Nutr. 2007;2(1):111–3.
Vue B, Zhang S, Chen QH. Flavonoids with therapeutic potential in prostate cancer [J]. Anticancer Agents Med Chem. 2016;16(10):1205–29.
Wenzel U, Kuntz S, Brendel MD, et al. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells [J]. Cancer Res. 2000;60(14):3823–31.
Dal-Ho H, Hirofumi T, Yamada K. Inhibition of environmental estrogen-induced proliferation of human breast carcinoma mcf-7 cells by flavonoids [J]. Vitro Cell Dev Biol Anim. 2001;37(5):275–82.
Yin F, Giuliano AE, Van Herle AJ. Signal pathways involved in apigenin inhibition of growth and induction of apoptosis of human anaplastic thyroid cancer cells (aro) [J]. Anticancer Res. 1999;19(5b):4297–303.
Woo H-H, Jeong BR, Hawes MC. Flavonoids: from cell cycle regulation to biotechnology [J]. Biotech Lett. 2005;27(6):365.
Cho HJ, Suh DS, Moon SH, et al. Silibinin inhibits tumor growth through downregulation of extracellular signal-regulated kinase and akt in vitro and in vivo in human ovarian cancer cells [J]. J Agric Food Chem. 2013;61(17):4089–96.
Petrick JL, Steck SE, Bradshaw PT, et al. Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the united states of america (USA) [J]. Br J Cancer. 2015;112(7):1291–300.
Cibin TR, Devi DG, Abraham A. Chemoprevention of skin cancer by the flavonoid fraction of saraca asoka [J]. Phytother Res. 2010;24(5):666–72.
Rossi M, Rosato V, Bosetti C, et al. Flavonoids, proanthocyanidins, and the risk of stomach cancer [J]. Cancer Causes Control. 2010;21(10):1597–604.
Surh YJ. Cancer chemoprevention with dietary phytochemicals [J]. Nat Rev Cancer. 2003;3(10):768–80.
Tsyrlov IB, Mikhailenko VM, Gelboin HV. Isozyme- and species-specific susceptibility of cdna-expressed cyp1a p-450s to different flavonoids [J]. Biochim Biophys Acta. 1994;1205(2):325–35.
Manthey JA, Grohmann K, Guthrie N. Biological properties of citrus flavonoids pertaining to cancer and inflammation [J]. Curr Med Chem. 2001;8(2):135–53.
Iwashita K, Kobori M, Yamaki K, et al. Flavonoids inhibit cell growth and induce apoptosis in b16 melanoma 4a5 cells [J]. Biosci Biotechnol Biochem. 2000;64(9):1813–20.
Lee WR, Shen SC, Lin HY, et al. Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and ca(2+)-dependent endonuclease [J]. Biochem Pharmacol. 2002;63(2):225–36.
Konig A, Schwartz GK, Mohammad RM, et al. The novel cyclin-dependent kinase inhibitor flavopiridol downregulates bcl-2 and induces growth arrest and apoptosis in chronic b-cell leukemia lines [J]. Blood. 1997;90(11):4307–12.
Wang HK. The therapeutic potential of flavonoids [J]. Expert Opin Investig Drugs. 2000;9(9):2103–19.
Le Marchand L, Murphy SP, Hankin JH, et al. Intake of flavonoids and lung cancer [J]. J Natl Cancer Inst. 2000;92(2):154–60.
Sun XY, Plouzek CA, Henry JP, et al. Increased udp-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin a in prostate cancer cells [J]. Cancer Res. 1998;58(11):2379–84.
Bu-Abbas A, Clifford MN, Walker R, et al. Contribution of caffeine and flavanols in the induction of hepatic phase ii activities by green tea [J]. Food Chem Toxicol. 1998;36(8):617–21.
Fotsis T, Pepper MS, Aktas E, et al. Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis [J]. Cancer Res. 1997;57(14):2916–21.
Kim MH. Flavonoids inhibit vegf/bfgf-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases [J]. J Cell Biochem. 2003;89(3):529–38.
Schindler R, Mentlein R. Flavonoids and vitamin e reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells [J]. J Nutr. 2006;136(6):1477–82.
Kioka N, Hosokawa N, Komano T, et al. Quercetin, a bioflavonoid, inhibits the increase of human multidrug resistance gene (mdr1) expression caused by arsenite [J]. FEBS Lett. 1992;301(3):307–9.
Shapiro AB, Ling V. Effect of quercetin on hoechst 33342 transport by purified and reconstituted p-glycoprotein [J]. Biochem Pharmacol. 1997;53(4):587–96.
Lee JY, Kim HS, Song YS. Genistein as a potential anticancer agent against ovarian cancer [J]. J Tradit Complement Med. 2012;2(2):96–104.
Adjakly M, Ngollo M, Boiteux JP, et al. Genistein and daidzein: different molecular effects on prostate cancer [J]. Anticancer Res. 2013;33(1):39–44.
Hwang KA, Choi KC. Anticarcinogenic effects of dietary phytoestrogens and their chemopreventive mechanisms [J]. Nutr Cancer. 2015;67(5):796–803.
Martin PM, Horwitz KB, Ryan DS, et al. Phytoestrogen interaction with estrogen receptors in human breast cancer cells [J]. Endocrinology. 1978;103(5):1860–7.
Peterson G, Barnes S. Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells [J]. Cell Growth Differ. 1996;7(10):1345–51.
Biedermann D, Vavrikova E, Cvak L, et al. Chemistry of silybin [J]. Nat Prod Rep. 2014;31(9):1138–57.
Zarrelli A, Romanucci V, De Napoli L, et al. Synthesis of new silybin derivatives and evaluation of their antioxidant properties [J]. Helv Chim Acta. 2015;98(3):399–409.
Comelli MC, Mengs U, Schneider C, et al. Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy [J]. Integr Cancer Ther. 2007;6(2):120–9.
Deep G, Agarwal R. Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential against cancer [J]. Cancer Metastasis Rev. 2010;29(3):447–63.
Hoh C, Boocock D, Marczylo T, et al. Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences [J]. Clin Cancer Res. 2006;12(9):2944–50.
Flaig TW, Glode M, Gustafson D, et al. A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer [J]. Prostate. 2010;70(8):848–55.
Manna SK, Mukhopadhyay A, Van NT, et al. Silymarin suppresses tnf-induced activation of nf-kappa b, c-jun n-terminal kinase, and apoptosis [J]. J Immunol. 1999;163(12):6800–9.
Ahmad N, Gali H, Javed S, et al. Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression [J]. Biochem Biophys Res Commun. 1998;247(2):294–301.
Zhu W, Zhang JS, Young CY. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line lncap [J]. Carcinogenesis. 2001;22(9):1399–403.
Li L, Zeng J, Gao Y, et al. Targeting silibinin in the antiproliferative pathway [J]. Expert Opin Investig Drugs. 2010;19(2):243–55.
Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives [J]. Antioxidants (Basel, Switzerland). 2015;4(1):204–47.
Bang CI, Paik SY, Sun DI, et al. Cell growth inhibition and down-regulation of survivin by silibinin in a laryngeal squamous cell carcinoma cell line [J]. Ann Otol Rhinol Laryngol. 2008;117(10):781–5.
Wu K, Zeng J, Li L, et al. Silibinin reverses epithelial-to-mesenchymal transition in metastatic prostate cancer cells by targeting transcription factors [J]. Oncol Rep. 2010;23(6):1545–52.
Harwood M, Danielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties [J]. Food Chem Toxicol. 2007;45(11):2179–205.
Zhao Y, Fan D, Zheng ZP, et al. 8-c-(e-phenylethenyl)quercetin from onion/beef soup induces autophagic cell death in colon cancer cells through erk activation. Mol Nutr Food Res. 2016;61(2).
Wang SF, Wu MY, Cai CZ, Li M, Lu JH. Autophagy modulators from traditional chinese medicine: mechanisms and therapeutic potentials for cancer and neurodegenerative diseases. J Ethnopharmacol. 2016;194:861–76.
Lou M, Zhang LN, Ji PG, et al. Quercetin nanoparticles induced autophagy and apoptosis through akt/erk/caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo [J]. Biomed Pharmacother. 2016;84:1–9.
Egert S, Rimbach G. Which sources of flavonoids: complex diets or dietary supplements? [J]. Adv Nutr: Int Rev J. 2011;2(1):8–14.
Gažák R, Fuksová K, Marhol P, et al. Preparative method for isosilybin isolation based on enzymatic kinetic resolution of silymarin mixture [J]. Process Biochem. 2013;48(1):184–9.
Zhou J, Du G, Chen J. Novel fermentation processes for manufacturing plant natural products [J]. Curr Opin Biotechnol. 2014;25:17–23.
Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety [J]. Annu Rev Nutr. 2002;22(1):19–34.
Zhu Y, Liu Y, Zhan Y, et al. Preparative isolation and purification of five flavonoid glycosides and one benzophenone galloyl glycoside from psidium guajava by high-speed counter-current chromatography (hsccc) [J]. Molecules (Basel, Switzerland). 2013;18(12):15648–61.
Markham KR. Isolation techniques for flavonoids [M]. In: Harborne JB, Mabry TJ, Mabry H, editors. The flavonoids. Boston: Springer; 1975. p. 1–44.
Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads [J]. Biochim Biophys Acta. 2013;1830(6):3670–95.
Hossain MA, Mizanur Rahman SM. Isolation and characterisation of flavonoids from the leaves of medicinal plant orthosiphon stamineus [J]. Arab J Chem. 2015;8(2):218–21.
Ferreyra MLF, Rius SP, Casati P. Flavonoids: biosynthesis, biological functions, and biotechnological applications [J]. Front Plant Sci. 2012;3:222.
Koes RE, Quattrocchio F, Mol JN. The flavonoid biosynthetic pathway in plants: function and evolution [J]. BioEssays. 1994;16(2):123–32.
Quattrocchio F, Baudry A, Lepiniec L, et al. The regulation of flavonoid biosynthesis [M]. The science of flavonoids. Berlin: Springer; 2006. p. 97–122.
Stobiecki M, Kachlicki P. Isolation and identification of flavonoids [M]. The science of flavonoids. Berlin: Springer; 2006. p. 47–69.
Gates MA, Vitonis AF, Tworoger SS, et al. Flavonoid intake and ovarian cancer risk in a population-based case-control study [J]. Int J Cancer. 2009;124(8):1918–25.
Gates MA, Tworoger SS, Hecht JL, et al. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer [J]. Int J Cancer. 2007;121(10):2225–32.
Molina-Montes E, Sanchez MJ, Zamora-Ros R, et al. Flavonoid and lignan intake and pancreatic cancer risk in the european prospective investigation into cancer and nutrition cohort [J]. Int J Cancer. 2016;139(7):1480–92.
Lei L, Yang Y, He H, Chen E, Du L, Dong J, Yang J. Flavan-3-ols consumption and cancer risk: a meta-analysis of epidemiologic studies. Oncotarget. 2016;7(45):73573–92.
Theodoratou E, Kyle J, Cetnarskyj R, et al. Dietary flavonoids and the risk of colorectal cancer [J]. Cancer Epidemiol Biomark Prev. 2007;16(4):684–93.
Zamora-Ros R, Barupal DK, Rothwell JA, Jenab M, Fedirko V, Romieu I, Aleksandrova K, Overvad K, Kyro C, Tjonneland A, Affret A, His M, Boutron-Ruault MC, Katzke V, Kuhn T, Boeing H, Trichopoulou A, Naska A, Kritikou M, Saieva C, Agnoli C, Santucci de Magistris M, Tumino R, Fasanelli F, Weiderpass E, Skeie G, Merino S, Jakszyn P, Sanchez MJ, Dorronsoro M, Navarro C, Ardanaz E, Sonestedt E, Ericson U, Maria Nilsson L, Boden S, Bueno-de-Mesquita HB, Peeters PH, Perez-Cornago A, Wareham NJ, Khaw KT, Freisling H, Cross AJ, Riboli E, Scalbert A. Dietary flavonoid intake and colorectal cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort. Int J Cancer. 2017;140(8):1836–44.
Shin A, Lee J, Lee J, et al. Isoflavone and soyfood intake and colorectal cancer risk: a case-control study in korea [J]. PLoS ONE. 2015;10(11):e0143228.
Zamora-Ros R, Not C, Guinó E, et al. Association between habitual dietary flavonoid and lignan intake and colorectal cancer in a spanish case–control study (the bellvitge colorectal cancer study) [J]. Cancer Causes Control. 2013;24(3):549–57.
Woo HD, Kim J. Dietary flavonoid intake and risk of stomach and colorectal cancer [J]. World J Gastroenterol. 2013;19(7):1011–9.
Simons CC, Hughes LA, Arts IC, et al. Dietary flavonol, flavone and catechin intake and risk of colorectal cancer in the netherlands cohort study [J]. Int J Cancer. 2009;125(12):2945–52.
Hirvonen T, Virtamo J, Korhonen P, et al. Flavonol and flavone intake and the risk of cancer in male smokers (finland) [J]. Cancer Causes Control. 2001;12(9):797–802.
Nimptsch K, Zhang X, Cassidy A, et al. Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts [J]. Am J Clin Nutr. 2016;103(1):184–91.
Kempkes M, Golka K, Reich S, et al. Glutathione s-transferase gstm1 and gstt1 null genotypes as potential risk factors for urothelial cancer of the bladder [J]. Arch Toxicol. 1996;71:123–6.
Yu CP, Shia C-S, Tsai S-Y, Hou YC. Pharmacokinetics and relative bioavailability of flavonoids between two dosage forms of gegen-qinlian-tang in rats. Evid-Based Complement Altern Med. 2012;2012:308018.
Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships [J]. J Nutr Biochem. 2002;13(10):572–84.
Cai X, Fang Z, Dou J, et al. Bioavailability of quercetin: problems and promises [J]. Curr Med Chem. 2013;20(20):2572–82.
Mauludin R, Müller RH, Keck CM. Kinetic solubility and dissolution velocity of rutin nanocrystals [J]. Eur J Pharm Sci. 2009;36(4):502–10.
Gil-Izquierdo A, Gil MI, Ferreres F, et al. In vitro availability of flavonoids and other phenolics in orange juice [J]. J Agric Food Chem. 2001;49(2):1035–41.
Mandalari G, Tomaino A, Rich GT, et al. Polyphenol and nutrient release from skin of almonds during simulated human digestion [J]. Food Chem. 2010;122(4):1083–8.
King RA, Bursill DB. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans [J]. Am J Clin Nutr. 1998;67(5):867–72.
Gee JM, DuPont MS, Day AJ, et al. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway [J]. J Nutr. 2000;130(11):2765–71.
Spencer JPE. Metabolism of tea flavonoids in the gastrointestinal tract [J]. J Nutr. 2003;133(10):3255S–61S.
Olthof MR, Hollman PC, Buijsman MN, et al. Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans [J]. J Nutr. 2003;133(6):1806–14.
Aura AM, Martin-Lopez P, O’Leary KA, et al. In vitro metabolism of anthocyanins by human gut microflora [J]. Eur J Nutr. 2005;44(3):133–42.
Winter J, Moore LH, Dowell VR Jr, et al. C-ring cleavage of flavonoids by human intestinal bacteria [J]. Appl Environ Microbiol. 1989;55(5):1203–8.
Gonthier MP, Verny MA, Besson C, et al. Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats [J]. J Nutr. 2003;133(6):1853–9.
Kim DH, Jung EA, Sohng IS, et al. Intestinal bacterial metabolism of flavonoids and its relation to some biological activities [J]. Arch Pharm Res. 1998;21(1):17–23.
Ueno I, Nakano N, Hirono I. Metabolic fate of [14c] quercetin in the aci rat [J]. Jpn J Exp Med. 1983;53(1):41–50.
Boulton DW, Walle UK, Walle T. Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism [J]. J Pharm Pharmacol. 1999;51(3):353–9.
Zhu H-J, Brinda BJ, Chavin KD, et al. An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: a dose escalation study [J]. Drug Metab Dispos. 2013;41(9):1679–85.
Dixit N, Baboota S, Kohli K, et al. Silymarin: a review of pharmacological aspects and bioavailability enhancement approaches [J]. Indian J Pharmacol. 2007;39(4):172.
Spencer JP, Schroeter H, Rechner AR, et al. Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo [J]. Antioxid Redox Signal. 2001;3(6):1023–39.
Gawande S, Kale A, Kotwal S. Effect of nutrient mixture and black grapes on the pharmacokinetics of orally administered (-)epigallocatechin-3-gallate from green tea extract: a human study [J]. Phytother Res. 2008;22(6):802–8.
Nunes T, Almeida L, Rocha JF, et al. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects [J]. J Clin Pharmacol. 2009;49(12):1477–82.
Decker EA. Phenolics: prooxidants or antioxidants? [J]. Nutr Rev. 1997;55(11 Pt 1):396–8.
Fresco P, Borges F, Diniz C, et al. New insights on the anticancer properties of dietary polyphenols [J]. Med Res Rev. 2006;26(6):747–66.
Křížková J, Burdová K, Stiborová M, et al. The effects of selected flavonoids on cytochromes p450 in rat liver and small intestine [J]. Interdiscip Toxicol. 2009;2(3):201–4.
Jiang W, Hu M. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase ii metabolic pathways [J]. RSC Adv. 2012;2(21):7948–63.
Xiao J, Ni X, Kai G, et al. A review on structure–activity relationship of dietary polyphenols inhibiting α-amylase [J]. Crit Rev Food Sci Nutr. 2013;53(5):497–506.
Xiao J, Kai G, Yamamoto K, et al. Advance in dietary polyphenols as α-glucosidases inhibitors: a review on structure-activity relationship aspect [J]. Crit Rev Food Sci Nutr. 2013;53(8):818–36.
Xiao JB, Huo JL, Yang F, et al. Noncovalent interaction of dietary polyphenols with bovine hemoglobin in vitro: molecular structure/property–affinity relationship aspects [J]. J Agric Food Chem. 2011;59(15):8484–90.
Morris ME, Zhang S. Flavonoid–drug interactions: effects of flavonoids on abc transporters [J]. Life Sci. 2006;78(18):2116–30.
Duda-Chodak A, Tarko T, Satora P, et al. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review [J]. Eur J Nutr. 2015;54(3):325–41.
Xiao J, Kai G. A review of dietary polyphenol-plasma protein interactions: characterization, influence on the bioactivity, and structure-affinity relationship [J]. Crit Rev Food Sci Nutr. 2012;52(1):85–101.
Xiao J, Cao H, Wang Y, et al. Glycosylation of dietary flavonoids decreases the affinities for plasma protein [J]. J Agric Food Chemistry. 2009;57(15):6642–8.
Sun Y-L, Patel A, Kumar P, et al. Role of abc transporters in cancer chemotherapy [J]. Chinese J Cancer. 2012;31(2):51–7.
Alfarouk KO, Stock C-M, Taylor S, et al. Resistance to cancer chemotherapy: failure in drug response from adme to p-gp [J]. Cancer Cell Int. 2015;15(1):71.
Kathawala RJ, Gupta P, Ashby CR Jr, et al. The modulation of abc transporter-mediated multidrug resistance in cancer: a review of the past decade [J]. Drug Resist Updates. 2015;18:1–17.
Klein I, Sarkadi B, Varadi A. An inventory of the human abc proteins [J]. Biochem Biophys Acta. 1999;1461(2):237–62.
Vasiliou V, Vasiliou K, Nebert DW. Human atp-binding cassette (abc) transporter family [J]. Hum Genom. 2009;3(3):281–90.
Rice AJ, Park A, Pinkett HW. Diversity in abc transporters: type i, ii and iii importers [J]. Crit Rev Biochem Mol Biol. 2014;49(5):426–37.
Chen Z, Shi T, Zhang L, et al. Mammalian drug efflux transporters of the atp binding cassette (abc) family in multidrug resistance: a review of the past decade [J]. Cancer Lett. 2016;370(1):153–64.
Klappe K, Hummel I, Hoekstra D, et al. Lipid dependence of abc transporter localization and function [J]. Chem Phys Lipid. 2009;161(2):57–64.
Murakami T, Takano M. Intestinal efflux transporters and drug absorption [J]. Expert Opin Drug Metab Toxicol. 2008;4(7):923–39.
Russel FG. Transporters: Importance in drug absorption, distribution, and removal [M]. Enzyme-and transporter-based drug-drug interactions. Berlin: Springer; 2010. p. 27–49.
Alvarez AI, Real R, Pérez M, et al. Modulation of the activity of abc transporters (p-glycoprotein, mrp2, bcrp) by flavonoids and drug response [J]. J Pharm Sci. 2010;99(2):598–617.
Cermak R, Wolffram S. The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms [J]. Curr Drug Metab. 2006;7(7):729–44.
Gatouillat G, Magid AA, Bertin E, et al. Medicarpin and millepurpan, two flavonoids isolated from medicago sativa, induce apoptosis and overcome multidrug resistance in leukemia p388 cells [J]. Phytomedicine. 2015;22(13):1186–94.
Dash RP, Ellendula B, Agarwal M, et al. Increased intestinal p-glycoprotein expression and activity with progression of diabetes and its modulation by epigallocatechin-3-gallate: Evidence from pharmacokinetic studies [J]. Eur J Pharmacol. 2015;767:67–76.
Wink M, Ashour ML, El-Readi MZ. Secondary metabolites from plants inhibiting abc transporters and reversing resistance of cancer cells and microbes to cytotoxic and antimicrobial agents. Front Microbiol. 2012;3:130.
Schoonbeek HJ, Raaijmakers JM, De Waard MA. Fungal abc transporters and microbial interactions in natural environments [J]. Mol Plant Microbe Interact. 2002;15(11):1165–72.
Marzolini C, Paus E, Buclin T, et al. Polymorphisms in human mdr1 (p-glycoprotein): recent advances and clinical relevance [J]. Clin Pharmacol Ther. 2004;75(1):13–33.
Choi J-S, Han H-K. Enhanced oral exposure of diltiazem by the concomitant use of naringin in rats [J]. Int J Pharm. 2005;305(1):122–8.
Ofer M, Wolffram S, Koggel A, et al. Modulation of drug transport by selected flavonoids: involvement of p-gp and oct? [J]. Eur J Pharm Sci. 2005;25(2):263–71.
Spahn-Langguth H, Langguth P. Grapefruit juice enhances intestinal absorption of the p-glycoprotein substrate talinolol [J]. Eur J Pharm Sci. 2001;12(4):361–7.
Brand W, Schutte ME, Williamson G, et al. Flavonoid-mediated inhibition of intestinal abc transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients [J]. Biomed Pharmacother. 2006;60(9):508–19.
Li Y, Paxton JW. The effects of flavonoids on the abc transporters: consequences for the pharmacokinetics of substrate drugs [J]. Expert Opin Drug Metab Toxicol. 2013;9(3):267–85.
Schexnayder C, Stratford RE. Genistein and glyceollin effects on abcc2 (mrp2) and abcg2 (bcrp) in caco-2 cells [J]. Int J Environ Res Public Health. 2015;13(1):17.
Bernardo J, Valentao P, Grosso C, et al. Flavonoids in neurodegeneration: Limitations and strategies to cross cns barriers [J]. Curr Med Chem. 2016;23:4151–74.
Tan ZR, Zhou YX, Liu J, et al. The influence of abcb1 polymorphism c3435t on the pharmacokinetics of silibinin [J]. J Clin Pharm Ther. 2015;40(6):685–8.
Zanger UM, Schwab M. Cytochrome p450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation [J]. Pharmacol Ther. 2013;138(1):103–41.
Rendic S. Summary of information on human cyp enzymes: human p450 metabolism data [J]. Drug Metab Rev. 2002;34(1–2):83–448.
Miniscalco A, Lundahl J, Regårdh C, et al. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice [J]. J Pharmacol Exp Ther. 1992;261(3):1195–9.
Schubert W, Eriksson U, Edgar B, et al. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17β-estradiol [J]. Eur J Drug Metab Pharmacokinet. 1995;20(3):219–24.
Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: forbidden fruit or avoidable consequences? [J]. CMAJ. 2013;185(4):309–16.
Dong J, Zhang Q, Cui Q, et al. Flavonoids and naphthoflavonoids: wider roles in the modulation of cytochrome p450 family 1 enzymes [J]. ChemMedChem. 2016;11(19):2102–18.
Arora S, Taneja I, Challagundla M, et al. In vivo prediction of cyp-mediated metabolic interaction potential of formononetin and biochanin a using in vitro human and rat cyp450 inhibition data [J]. Toxicol Lett. 2015;239(1):1–8.
Shimada T, Tanaka K, Takenaka S, et al. Structure–function relationships of inhibition of human cytochromes p450 1a1, 1a2, 1b1, 2c9, and 3a4 by 33 flavonoid derivatives [J]. Chem Res Toxicol. 2010;23(12):1921–35.
Takemura H, Itoh T, Yamamoto K, et al. Selective inhibition of methoxyflavonoids on human cyp1b1 activity [J]. Bioorg Med Chem. 2010;18(17):6310–5.
Androutsopoulos VP, Papakyriakou A, Vourloumis D, et al. Comparative cyp1a1 and cyp1b1 substrate and inhibitor profile of dietary flavonoids [J]. Bioorg Med Chem. 2011;19(9):2842–9.
Sridhar J, Ellis J, Dupart P, et al. Development of flavone propargyl ethers as potent and selective inhibitors of cytochrome p450 enzymes 1a1 and 1a2 [J]. Drug Metab Lett. 2012;6(4):275–84.
Dong H, Lin W, Wu J, et al. Flavonoids activate pregnane × receptor-mediated cyp3a4 gene expression by inhibiting cyclin-dependent kinases in hepg2 liver carcinoma cells [J]. BMC Biochem. 2010;11(1):1.
Satsu H, Hiura Y, Mochizuki K, et al. Activation of pregnane x receptor and induction of mdr1 by dietary phytochemicals [J]. J Agric Food Chem. 2008;56(13):5366–73.
Li Y, Ross-Viola JS, Shay NF, et al. Human cyp3a4 and murine cyp3a11 are regulated by equol and genistein via the pregnane x receptor in a species-specific manner [J]. J Nutr. 2009;139(5):898–904.
Mooiman KD, Maas-Bakker RF, Moret EE, et al. Milk thistle’s active components silybin and isosilybin: novel inhibitors of pxr-mediated cyp3a4 induction [J]. Drug Metab Dispos. 2013;41(8):1494–504.
Korobkova EA. Effect of natural polyphenols on cyp metabolism: implications for diseases [J]. Chem Res Toxicol. 2015;28(7):1359–90.
Zeng M, Sun R, Basu S, et al. Disposition of flavonoids via recycling: direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides [J]. Mol Nutr Food Res. 2016;60(5):1006–19.
Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ [J]. Ther Adv Gastroenterol. 2013;6(4):295–308.
Lu K, Mahbub R, Fox JG. Xenobiotics: interaction with the intestinal microflora [J]. ILAR J. 2015;56(2):218–27.
Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions [J]. Science. 2012;336(6086):1262–7.
Scheline RR. Drug metabolism by intestinal microorganisms [J]. J Pharm Sci. 1968;57(12):2021–37.
Laparra JM, Sanz Y. Interactions of gut microbiota with functional food components and nutraceuticals [J]. Pharmacol Res. 2010;61(3):219–25.
Selma MV, Espin JC, Tomas-Barberan FA. Interaction between phenolics and gut microbiota: role in human health [J]. J Agric Food Chem. 2009;57(15):6485–501.
Lin W, Wang W, Yang H, et al. Influence of intestinal microbiota on the catabolism of flavonoids in mice. J Food Sci. 2016;81(12):H3026–34. doi:10.1111/1750-3841.13544.
Ozdal T, Sela DA, Xiao J, Boyacioglu D, Chen F, Capanoglu E. The reciprocal interactions between polyphenols and gut microbiota and effects on bioaccessibility. Nutrients. 2016;8(2):78.
Nurmi T, Mursu J, Heinonen M, et al. Metabolism of berry anthocyanins to phenolic acids in humans [J]. J Agric Food Chem. 2009;57(6):2274–81.
Atkinson C, Berman S, Humbert O, et al. In vitro incubation of human feces with daidzein and antibiotics suggests interindividual differences in the bacteria responsible for equol production [J]. J Nutr. 2004;134(3):596–9.
Lampe JW. Interindividual differences in response to plant-based diets: implications for cancer risk [J]. Am J Clin Nutr. 2009;89(5):1553s–7s.
Simons AL, Renouf M, Hendrich S, et al. Human gut microbial degradation of flavonoids: structure-function relationships [J]. J Agric Food Chem. 2005;53(10):4258–63.
Duda-Chodak A. The inhibitory effect of polyphenols on human gut microbiota [J]. J Physiol Pharmacol. 2012;63(5):497–503.
Fotschki B, Juskiewicz J, Sojka M, et al. Ellagitannins and flavan-3-ols from raspberry pomace modulate caecal fermentation processes and plasma lipid parameters in rats [J]. Molecules (Basel, Switzerland). 2015;20(12):22848–62.
Esposito D, Damsud T, Wilson M, et al. Black currant anthocyanins attenuate weight gain and improve glucose metabolism in diet-induced obese mice with intact, but not disrupted, gut microbiome [J]. J Agric Food Chem. 2015;63(27):6172–80.
Bridle P, Timberlake CF. Anthocyanins as natural food colours—selected aspects [J]. Food Chem. 1997;58(1):103–9.
Pappas EL. Improving stability of color, total phenolics, flavonoids and ascorbic acid in cranberry juice cocktail via alternative processing and storage techniques. New Brunswick: Rutgers University-Graduate School; 2016.
Ruenroengklin N, Zhong J, Duan X, et al. Effects of various temperatures and ph values on the extraction yield of phenolics from litchi fruit pericarp tissue and the antioxidant activity of the extracted anthocyanins [J]. Int J Mol Sci. 2008;9(7):1333–41.
Ghasemzadeh A, Jaafar HZ, Rahmat A, et al. Effect of different light intensities on total phenolics and flavonoids synthesis and anti-oxidant activities in young ginger varieties (zingiber officinale roscoe) [J]. Int J Mol Sci. 2010;11(10):3885–97.
Maini S, Hodgson HL, Krol ES. The uva and aqueous stability of flavonoids is dependent on b-ring substitution [J]. J Agric Food Chem. 2012;60(28):6966–76.
Perez-Jimenez J, Serrano J, Tabernero M, et al. Bioavailability of phenolic antioxidants associated with dietary fiber: plasma antioxidant capacity after acute and long-term intake in humans [J]. Plant Foods Hum Nutr. 2009;64(2):102–7.
Palafox-Carlos H, Ayala-Zavala JF, González-Aguilar GA. The role of dietary fiber in the bioaccessibility and bioavailability of fruit and vegetable antioxidants [J]. J Food Sci. 2011;76(1):R6–15.
Saura-Calixto F. Dietary fiber as a carrier of dietary antioxidants: an essential physiological function [J]. J Agric Food Chem. 2011;59(1):43–9.
Yang L, Cao YL, Jiang JG, et al. Response surface optimization of ultrasound-assisted flavonoids extraction from the flower of citrus aurantium l. Var. Amara engl [J]. J Sep Sci. 2010;33(9):1349–55.
Liu Y, Wang H, Cai X. Optimization of the extraction of total flavonoids from scutellaria baicalensis georgi using the response surface methodology [J]. J Food Sci Technol. 2015;52(4):2336–43.
Wang X, Wu Y, Chen G, et al. Optimisation of ultrasound assisted extraction of phenolic compounds from sparganii rhizoma with response surface methodology [J]. Ultrason Sonochem. 2013;20(3):846–54.
Arif Khan SER, John ML and Barbara LK. 471914 nanoharvesting of polyphenolic flavonoids from solidago nemoralis hairy root cultures using functionalized mesoporous silica nanoparticles. 2016 AIChE annual meeting 2016. San Francisco: American Institute of Chemical Engineers; 2016.
Kurepa J, Nakabayashi R, Paunesku T, et al. Direct isolation of flavonoids from plants using ultra-small anatase tio(2) nanoparticles [J]. Plant J. 2014;77(3):443–53.
Wang J, Zhao Y-M, Guo C-Y, et al. Ultrasound-assisted extraction of total flavonoids from Inula helenium [J]. Pharmacogn Mag. 2012;8(30):166.
Zheng L-L, Wang D, Li YY, et al. Ultrasound-assisted extraction of total flavonoids from Aconitum gymnandrum [J]. Pharmacogn Mag. 2014;10(Suppl 1):S141.
Wu J, Du G, Zhou J, et al. Systems metabolic engineering of microorganisms to achieve large-scale production of flavonoid scaffolds [J]. J Biotechnol. 2014;188:72–80.
Santos CN, Koffas M, Stephanopoulos G. Optimization of a heterologous pathway for the production of flavonoids from glucose [J]. Metab Eng. 2011;13(4):392–400.
Wu J, Du G, Zhou J, et al. Metabolic engineering of Escherichia coli for (2s)-pinocembrin production from glucose by a modular metabolic strategy [J]. Metab Eng. 2013;16:48–55.
Vannelli T, Wei Qi W, Sweigard J, et al. Production of p-hydroxycinnamic acid from glucose in Saccharomyces cerevisiae and Escherichia coli by expression of heterologous genes from plants and fungi [J]. Metab Eng. 2007;9(2):142–51.
Koopman F, Beekwilder J, Crimi B, et al. De novo production of the flavonoid naringenin in engineered Saccharomyces cerevisiae [J]. Microb Cell Fact. 2012;11:155.
Wang Y, Chen S, Yu O. Metabolic engineering of flavonoids in plants and microorganisms [J]. Appl Microbiol Biotechnol. 2011;91(4):949–56.
Thilakarathna SH, Rupasinghe HPV. Flavonoid bioavailability and attempts for bioavailability enhancement [J]. Nutrients. 2013;5(9):3367–87.
Olthof MR, Hollman PC, Vree TB, et al. Bioavailabilities of quercetin-3-glucoside and quercetin-4′-glucoside do not differ in humans [J]. J Nutr. 2000;130(5):1200–3.
VTatiraju D, Bagade VB, JKarambelkar P, et al. Natural bioenhancers: an overview [J]. J Pharmacogn Phytochem. 2013;2(3).
Rinwa P, Kumar A. Quercetin along with piperine prevents cognitive dysfunction, oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress. Arch Pharm Res. 2013. doi:10.1007/s12272-013-0205-4.
Lambert JD, Hong J, Kim DH, et al. Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice [J]. J Nutr. 2004;134(8):1948–52.
Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers [J]. Planta Med. 1998;64(4):353–6.
Vaidyanathan JB, Walle T. Cellular uptake and efflux of the tea flavonoid (-)epicatechin-3-gallate in the human intestinal cell line caco-2 [J]. J Pharmacol Exp Ther. 2003;307(2):745–52.
Gao S, Hu M. Bioavailability challenges associated with development of anti-cancer phenolics [J]. Mini Rev Med Chem. 2010;10(6):550–67.
Vue B, Zhang S, Zhang X, et al. Silibinin derivatives as anti-prostate cancer agents: synthesis and cell-based evaluations [J]. Eur J Med Chem. 2016;109:36–46.
Sy-Cordero AA, Graf TN, Runyon SP, et al. Enhanced bioactivity of silybin b methylation products [J]. Bioorg Med Chem. 2013;21(3):742–7.
Džubák P, Hajdúch M, Gažák R, et al. New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and p-glycoprotein modulatory activity [J]. Bioorg Med Chem. 2006;14(11):3793–810.
Althagafy HS, Graf TN, Sy-Cordero AA, et al. Semisynthesis, cytotoxicity, antiviral activity, and drug interaction liability of 7-o-methylated analogues of flavonolignans from milk thistle [J]. Bioorg Med Chem. 2013;21(13):3919–26.
Grande F, Parisi OI, Mordocco RA, et al. Quercetin derivatives as novel antihypertensive agents: synthesis and physiological characterization [J]. Eur J Pharm Sci. 2016;82:161–70.
Kim MK, Park K-S, Lee C, et al. Enhanced stability and intracellular accumulation of quercetin by protection of the chemically or metabolically susceptible hydroxyl groups with a pivaloxymethyl (pom) promoiety [J]. J Med Chem. 2010;53(24):8597–607.
Patra N, De U, Kang J-A, et al. A novel epoxypropoxy flavonoid derivative and topoisomerase ii inhibitor, mhy336, induces apoptosis in prostate cancer cells [J]. Eur J Pharmacol. 2011;658(2–3):98–107.
Kumar P, Sharma G, Kumar R, et al. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: biochemical, pharmacokinetic and biodistribution evidences [J]. Int J Pharm. 2016;515(1–2):307–14.
Balakrishnan S, Bhat FA, Raja Singh P, et al. Gold nanoparticle-conjugated quercetin inhibits epithelial-mesenchymal transition, angiogenesis and invasiveness via egfr/vegfr-2-mediated pathway in breast cancer [J]. Cell Prolif. 2016;49:678–97.
Kumar RP, Abraham A. Pvp- coated naringenin nanoparticles for biomedical applications-in vivo toxicological evaluations [J]. Chem-Biol Interact. 2016;257:110–8.
Chen LC, Chen YC, Su CY, et al. Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study [J]. Int J Nanomed. 2016;11:1557–66.
Macedo AS, Quelhas S, Silva AM, et al. Nanoemulsions for delivery of flavonoids: formulation and in vitro release of rutin as model drug [J]. Pharm Dev Technol. 2014;19(6):677–80.
Yi T, Liu C, Zhang J, et al. A new drug nanocrystal self-stabilized pickering emulsion for oral delivery of silybin [J]. Eur J Pharm Sci. 2017;96:420–7.
Zhu Y, Wang M, Zhang Y, et al. In vitro release and bioavailability of silybin from micelle-templated porous calcium phosphate microparticles [J]. AAPS PharmSciTech. 2016;17(5):1232–9.
Penalva R, Gonzalez-Navarro CJ, Gamazo C, et al. Zein nanoparticles for oral delivery of quercetin: pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia [J]. Nanomed Nanotechnol Biol Med. 2016;13(1):103–10.
Filippi A, Petrussa E, Rajcevic U, et al. Flavonoid interaction with a chitinase from grape berry skin: protein identification and modulation of the enzymatic activity [J]. Molecules (Basel, Switzerland). 2016;21(10):1300.
Tang L, Li S, Bi H, et al. Interaction of cyanidin-3-o-glucoside with three proteins [J]. Food Chem. 2016;196:550–9.
Arroyo-Maya IJ, Campos-Teran J, Hernandez-Arana A, et al. Characterization of flavonoid-protein interactions using fluorescence spectroscopy: binding of pelargonidin to dairy proteins [J]. Food Chem. 2016;213:431–9.
Kanakis CD, Tarantilis PA, Polissiou MG, et al. Probing the binding sites of resveratrol, genistein, and curcumin with milk beta-lactoglobulin [J]. J Biomol Struct Dyn. 2013;31(12):1455–66.
He Z, Xu M, Zeng M, et al. Interactions of milk alpha- and beta-casein with malvidin-3-o-glucoside and their effects on the stability of grape skin anthocyanin extracts [J]. Food Chem. 2016;199:314–22.
Devendra S, Mohan SMR, Ajay S, et al. Quercetin-phospholipid complex: an amorphous pharmaceutical system in herbal drug delivery [J]. Curr Drug Discov Technol. 2012;9(1):17–24.
Semalty A, Semalty M, Rawat BS, et al. Pharmacosomes: the lipid-based new drug delivery system [J]. Expert Opin Drug Deliv. 2009;6(6):599–612.
Zhang K, Zhang M, Liu Z, et al. Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in sd rats [J]. Fitoterapia. 2016;113:102–9.
HA, CRA, and AKT conceptualized the idea. HA and AKT wrote the paper. AKT and CRA proofed and revised the paper. All authors read and approved the final manuscript.
We thank Ms. Charisse Montgomery, University of Toledo for critical reading of this manuscript. This work was supported by seed-fund to AKT from Department of Pharmacology and Experimental Therapeutics at UT.
The authors declare that they have no competing interests.
An erratum to this article is available at https://doi.org/10.1186/s40880-017-0237-0.
About this article
Cite this article
Amawi, H., Ashby, C.R. & Tiwari, A.K. Cancer chemoprevention through dietary flavonoids: what’s limiting?. Chin J Cancer 36, 50 (2017). https://doi.org/10.1186/s40880-017-0217-4