Next Article in Journal
Comparative Study of Essential Oils Extracted from Egyptian Basil Leaves (Ocimum basilicum L.) Using Hydro-Distillation and Solvent-Free Microwave Extraction
Next Article in Special Issue
Olive Oil and the Hallmarks of Aging
Previous Article in Journal
Total Synthesis of Chiral Falcarindiol Analogues Using BINOL-Promoted Alkyne Addition to Aldehydes
Previous Article in Special Issue
Analgesic Potential of Essential Oils
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine

1
Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon 200704, Korea
2
Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida 203201, India
3
Amity Institute of Nanotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh 201313, India
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2016, 21(1), 108; https://doi.org/10.3390/molecules21010108
Submission received: 14 November 2015 / Revised: 24 December 2015 / Accepted: 7 January 2016 / Published: 19 January 2016
(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Natural Products)

Abstract

:
Phytochemicals as dietary constituents are being explored for their cancer preventive properties. Quercetin is a major constituent of various dietary products and recently its anti-cancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. Quercetin is known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, quercetin possesses great medicinal value, its applications as a therapeutic drug are limited. Problems like low oral bioavailability and poor aqueous solubility make quercetin an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of quercetin is also a major barrier for its clinical translation. Hence, to overcome these disadvantages quercetin-based nanoformulations are being considered in recent times. Nanoformulations of quercetin have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site. Herein we have tried to summarize various methods utilized for nanofabrication of quercetin formulations and for stable and sustained delivery of quercetin. We have also highlighted the various desirable measures for its use as a promising onco-therapeutic agent.

1. Introduction

The medicinal properties of various phytochemicals, such as anti-oxidative, anti-inflammatory, antimicrobial and anticancer activities, have been known to mankind since ancient times. Flavonoids are well known phytochemicals possessing medicinal properties and are found in fruits and vegetables as secondary metabolites. To date, around 9000 types of flavonoids are classified in natural foods [1,2]. Quercetin is among these dietary flavonoids and is attracting increasing interest as a novel medicinal biomolecule with diverse therapeutic properties [3]. In a general daily diet comprising fruits and vegetables, quercetin is available as conjugated isoforms bound to alcohols and sugars [4]. These isoforms get hydrolyzed in the gastrointestinal tract and are absorbed and metabolized into quercetin aglycone and its other derivatives [5]. Among identified flavonoids quercetin is well known for possessing potent antioxidant activity, due to its ability to eliminate highly reactive oxygen species (O2and ONOO) [6,7]. Henceforth, the augmentation of mutated cell apoptosis by modulating cell signaling pathways is reported, which may result in the inhibition of cancer growth [8,9].
Worldwide, cancer has emerged as a foremost challenge for clinicians and is causing high mortality rates, both in developed as well as developing countries. Globally, in 2015, around 1.6 million new cases of cancer are expected to be diagnosed [10]. Available statistics account for more than 100 types of cancer known so far, including breast, colorectal, prostate, liver and lung cancers [11]. Regardless of new therapeutic approaches being progressively developed, effective cancer treatment therapies are still needed. Recently, it has been observed that a diet rich in fruits and vegetables reduces the risk of various types of cancer [12,13]. Thus, in the search for novel therapeutic drugs various studies have tried to explore the anticancer potential of natural compounds available from fruits and vegetables, such as phytochemicals [14,15,16]. As documented, these phytochemicals showed anticancer activities by modulating various cellular processes and interfering with cancer progression and metastasis (Figure 1) [17,18]. Among phytochemicals, quercetin has been reported to possess apoptotic activities against different cancer lines such as leukemia HL-60 [19], SW-480 colon cancer [20], 4T1 murine mammary cancer [21] and A431 epidermoid tumor cells [22]. However, the application of quercetin in pharmaceutics is still limited due to its poor bioavailability, hydrophobic nature and low stability [23]. Furthermore, quercetin tends to undergo high levels of enzymatic degradation in the gastrointestinal tract and have a low circulation time in the body [24,25]. Some studies also reported the toxic effects of quercetin at high doses in clinical phase trials [26]. Therefore, development of modified dosage forms of quercetin with increased bioavailability, long term stability, prolonged circulation time and decreased toxic effects at low doses is advocated.
Figure 1. Cellular processes modulated by quercetin (↓: downregulate and ↑: upregulate).
Figure 1. Cellular processes modulated by quercetin (↓: downregulate and ↑: upregulate).
Molecules 21 00108 g001
Nanotechnology-based drug delivery systems, loaded with phytochemicals, have recently gained interest in pharmaceutics due to their recuperative bioavailability and absorption potential [27,28]. Moreover, nanodelivery systems also protect the therapeutic molecule from being enzymatically metabolized, henceforth, increasing its stability and circulation time [29,30]. Conjugation of cancer cell specific targeting moieties with these nanodrugs also enable efficient selective uptake of drug by cancer cells as compared to normal cells [31]. Keeping all this in view, herein, we discuss the promising role of nanotechnology-based quercetin delivery systems for cancer therapy and the various merits and demerits associated with these approaches.

2. Chemistry of Quercetin and Its Derivatives

Quercetin (3,3′,4′,5,7-pentahydroxyflavone, Figure 2), is a naturally occurring flavonoid (flavone means yellow colour) and is a derivative of a flavone (2-phenylchromen-4-one). It contains five hydroxyl groups that are responsible for its biological activities and derivative diversification. Flavonoids generally consist of two benzene rings linked by pyran or pyrone rings [32]. In addition, the conformational analysis of quercetin showed the presence of 12 conformations of this molecule having Gibbs energies in the range of 0 to 5.33 kcal/mole. Furthermore, quercetin displays strong intramolecular H-bonding, explaining its biological multi-functionality and renders it the ability to form strong complex interactions, even with metals, affecting its bioavailability and transport [33]. Among these H-bonds, two bonds are with carbonyl groups and third one is between hydroxyl groups [34]. Naturally occurring quercetin acts as an auxin transport inhibitor and prevents the bilateral growth of plant embryos [35]. The most widely present derivatives of quercetin are glycosides and ethers [36,37]. Quercetin O-glycosides contains O-glycosidic bonds at the C-3 carbon hydroxyl group. Furthermore, a rare quercetin derivative form, a C-glycoside whose glycosylation site is the C-6 carbon, was also found in Ageratina calophylla [38]. Another rare derivative of quercetin, identified in the red alga Acanthophora spicifera and grapes (Vitis vinefera), is quercetin3-O-α-l-fucopyranoside where quercetin is attached to α-l-fucopyranosyl moiety through a glycosidic linkage at the C-3 position [39,40]. Moreover, the derivatives of quercetin glycosides may also contain acyl and sulfur substituents in addition to sugar moieties. In the case of ether derivatives the hydroxyl groups of quercetin are attached with alcohols via ether bonds. Although quercetin is lipophilic, the glycosylation of quercetin derivatives can increase the hydrophilicity and enable the molecules to transport through all parts of the plant [41].
Figure 2. Structure of quercetin and its derivatives.
Figure 2. Structure of quercetin and its derivatives.
Molecules 21 00108 g002
Previous studies identified the antioxidant abilities of quercetin, attributed by the presence of hydroxyl group in the A ring and a catechol group in the B ring [42]. This property enables quercetin to eliminate free oxygen species present in the body by transferring hydrogen or electrons or by chelating metal ions, thereby inhibiting enzymatic activities. Such scavenging of reactive oxygen species reduces inflammation and protects the cells with oxidative stress caused due to smoking or excessive exercise. Quercetin is also well known inhibitor of lipid peroxidation, preventing oxidation of low density lipoproteins (LDL) and damage of lipid membrane. Human cell membranes and LDL possess α-tocopherol (primary oxidant) which provides protection from deleterious effects of oxidation. Flavonoids can therefore slow the oxidation of lipoproteins by contributing the hydrogen atom to this α-tocopheryl radical [43,44]. In addition, it also elevates the level of glutathione and prevents the formation of free radicals. In consideration of the above facts, the antioxidant and free radical scavenging properties of quercetin have been studies to a vast extent, displaying the potential therapeutic benefits of quercetin.

3. Sources, Absorption and Metabolism of Quercetin

Quercetin is mainly found as glycosides in the edible parts of plants (such as quercetin glucosides or quercetin rutinoside, Figure 2). It is found in a variety of plants including berries, tea leaves, onion, broccoli and other fruits and leafy vegetable, but is mostly extracted from Sophoro japonica L. [45,46,47]. These fruits and vegetables are among the main food constituents in Western diet containing flavonoids (~350 ppm, expressed as aglycones) [48]. Besides, red wine, black tea and other fruit juices are also considered rich in dietary quercetin [49]. The average daily consumption of flavonoids, including flavones, flavanones, flavonols, catechins, anthocyanins, and biflavans in the United States amounts to around 1 g/day (expressed as quercetin equivalents), among which 160–175 mg/day is accounted for only by flavanones, flavones, and flavonols based on seasonal variations [50]. Individuals consuming quercetin-rich fruits and vegetables, such as tomatoes, may obtain about 200–500 mg/day of quercetin as a dietary constituent [51]. On the other hand, average intakes as low as <5 mg to 40 mg/day are also reported in some countries like Japan and Australia [52,53].
The therapeutic efficiency of quercetin may be defined by its bioavailability that is the amount of pharmacologically active drug absorbed upon oral administration [54]. Following ingestion of quercetin, the intestinal bacteria exert glycosidase activity and hydrolyze the sugar unit from β-glycosidase derivatives of quercetin to release quercetin in its aglycone form [55]. Quercetin aglycone is further absorbed via the stomach [56] or small intestine [57], either by passive diffusion or organic anion transporting polypeptide (OATP)-mediated absorption [58]. Absorbed quercetin aglycone is then metabolized into other pharmacologically active O-methyl, glucuronide or sulfate derivative forms in human plasma, such as 3′-methyl ether, quercetin 3-O-β-d-glucuronide (Q3GA) and quercetin-3′-sulfate (Figure 2) [5,59]. Intake of quercetin rich foods, such as onions, may increase the concentration of quercetin derivatives in plasma up to micromolar levels which are then metabolized in the liver and other organs [60]. Walle et al., suggested that a majority of quercetin metabolites in plasma are further metabolized in the lungs and are eliminated as CO2 (23.0%–81.1% of the oral quercetin dose). They also reported that only 3.3%–5.7% and 1.6%–4.6% of quercetin is recovered in urine and feces, respectively [61]. It was also observed that upon single gastric treatment of free quercetin at a dose of 50 mg/Kg body weight in male Sprague-Dawley rats, only 0.27 μg/mL free quercetin was quantified in plasma while 93% of the quercetin was metabolized within a time span of 1 h [62]. Studies also revealed the conversion of glucuronide and sulfate derivatives of quercetin into phenolic acids by colonic microflora before excretion [63]. In a study, about 21 different types of quercetin metabolites were recovered from urine after onion intake [64]. A previous study has also reported the presence of less than 8% of intragastric treated quercetin in kidneys and liver of rats [4]. The quercetin metabolism process within the body is thus quite rapid and consequently the available circulation time of the active quercetin molecule and its bioavailability is limited. Due to this rapid metabolic process, the observed pharmacological effect of quercetin in vitro is dissimilar to a great extent with that in vivo. Also, quercetin has low solubility in water (about 1 µg/mL) which further affects its therapeutic potential. Additionally, the solubility of quercetin in gastric and intestinal fluid was reported to be 5.5 µg/mL and 28.9 µg/mL, respectively. Henceforth, there is a need to increase the aqueous solubility and delay the metabolism of quercetin to maintain its levels in blood and other tissues for a prolonged time.
Besides medicinal properties, quercetin has also been investigated for its potential toxic effects such as pro-oxidant activity, mutagenicity, genotoxicity, inhibition of enzymes responsible for hormone metabolism, and mitochondrial toxicity [65]. Crebelli et al., demonstrated that plasma samples collected from rats, following oral administration of quercetin, lack mutagenic properties whereas fecal and urine samples displayed mutagenicity, suggesting that upon absorption quercetin may get metabolized into non-mutagenic derivatives [66]. Some studies also reported that the quercetin reveals renal toxicity at high doses during a phase I clinical trial [26]. On the contrary, Harwood et al. reviewed the non-toxic nature of quercetin in vivo compared to its in vitro behavior [67]. These uncertainties create a need for more advanced toxicity and safety analysis for quercetin before its application as therapeutic molecule in clinics.

4. Effect of Quercetin on Cancer Cell Biology

4.1. Inhibition of Cell Growth

Quercetin is known to exert antiproliferative effects on various types of cancer, both in vitro and in vivo. For example, in vitro studies demonstrated growth inhibitory effects of quercetin in the leukemia cell lines L1210 and P-388 [68], breast cancer cells [21], colon cancer cells COLO 20DM [69], ovarian cancer cells OVCA 433 [70], liver cancer cells HepG2 [71], epidermoidal cancer cells A431 [22] and gastric cancer cells [72]. Moreover, the antineoplastic activity of quercetin towards Walker carcinoma 256 was documented by Edwards et al. [73]. An antiproliferative effect of orally administered quercetin on pancreatic cancer cells was also observed in vivo by Angst [74]. The possible interaction of quercetin with signaling pathways which are responsible for cancer growth may lead to growth inhibition. Some of the signaling pathways explored are P13K/Akt, Her-2/neu, Wnt/β-catenin and EGFR. This flavonoid was found to inhibit mammalian target of rapamycin (mTOR) activity which gets hyperactivated during cancer and controls essential cell growth pathways, autophagy and biosynthesis of proteins, and interfere with the activation ofPI3K/Akt signaling pathway [75]. Suppression of P13K/Akt pathway was also demonstrated in other cell lines like breast cancer cell HCC1937 [76], SkBr3 cells [77], liver cancer cell HepG2 [71], and HL-60 leukemia [19], upon quercetin treatment. In addition, quercetin was also able to suppress the tumor growth in Dalton’s lymphoma mice by downregulating P13K-Akt-p53 pathway along with glycolytic metabolism [78]. Besides suppressing P13K/Akt pathway, quercetin can also downregulate human epidermal growth factor receptor 2 (Her-2/neu) in HER-2/neu overexpessing breast cancer cells which resulted in growth inhibition [77]. EGFR signaling pathway was also observed to be inhibited by quercetin in Sprague-Dawley male rats [79]. Moreover, quercetin induced inhibition of Wnt/β-catenin signaling pathway through the induction of Wnt antagonist Dickkopf (DKK) has also been illustrated which decreased the cell viability of 4T1 murine mammary cancer cells [21]. The involvement of quercetin regulated Wnt/beta-catenin signaling pathway in exhibiting antitumor effect in SW-480 colon cancer cells is also documented [20].
Besides modulating signaling pathways for proliferation, quercetin is also known to interfere with normal cell cycle progression which can lead to growth inhibition. Mu et al., evaluated that quercetin arrest cell cycle progression at G1 phase in HepG2 cells. Furthermore, they also showed that the growth inhibitory effect of quercetin is due to the increased expression of p21 and p27 (Cdk inhibitors) and p53 (tumor suppressor) [80]. Other studies also reported the cell cycle arrest at G2/M in HeLa cells [81], A549 lung cancer cells [82], SK0V ovarian cancer cells, U2OS osteosarcoma cells [83], HSC-3 and TW206 oral cancer cells after quercetin treatment [84]. From the mentioned literature one may conclude that quercetin can act as a potential growth inhibitor of tumor cells by regulating various cellular growth-associated biochemical events and arresting the cells during cell cycle events.

4.2. Inhibition of Metastasis

The utmost danger of cancer is its spread from one organ or part to other within a body through metastasis. Metastasis is related with the production of matrix metalloproteinases (MMPs) enzymes which are responsible for degrading extracellular matrix proteins in a variety of cells or tissues they encounter. They are classified into four types: stromelysins, gelatinases, collagenases and membrane type MMPs [85]. Earlier studies reported that MMPs are required for the invasion/metastasis of cancer cells, such as MMP-9 and MMP-2. Therefore, suppression of MMPs in cancer cells can diminish the chances of metastasis and can be a useful tool in cancer treatment. The potential of quercetin in inhibiting MMPs secretion was reported in various studies. Lin et al., identified that quercetin can prevent metastasis of breast cancer cells by suppressing the activation and migration of MMP-9 in 12-O-tetradecanoyl phorbol-13-acetate (TPA)-treated MCF-7 cells [86]. Quercetin also inhibited upregulation of MMP-9 by tumor necrosis factor (TNF)-α in JB6 P+ mouse epidermal cells [87]. Along with MMP-9, quercetin also decreased the secretion of MMP-2 in A431 epidermoid cancer cells [22], MiaPaCa-2 pancreatic cancer cells [88].

4.3. Induction of Apoptosis

Apoptosis is programmed cell death which plays a critical role in various physiological processes [89]. Specific gene activities regulate complex signaling pathways known to be responsible for cell apoptosis. Dysregulation of the apoptotic signaling results in apoptotic defects which can lead to cancer progression [90]. For cancer treatment, the major problem is the resistance of cancer cells against chemotherapeutic agents. Therefore, for efficient cancer treatment it is necessary to comprehend regulation of apoptotic signaling pathways via chemotherapeutic agents such as quercetin. There may be two pathways responsible for apoptosis: intrinsic (mitochondria mediated) or extrinsic (mediated by signals from other cells) (Figure 1). Studies have revealed that quercetin induces apoptosis in various types of cancer cells by regulating both extrinsic and intrinsic factors. Chien et al., demonstrated that quercetin tends to increase the synthesis of Bax (pro-apoptotic protein) and decrease the synthesis of Bcl-2 (anti-apoptotic protein) in MDA-MB-231 breast cancer cells [91]. Induction of apoptosis through AMP-activated protein kinase (AMPK) along with p-53 dependent apoptotic cell death was observed in HT-29 colon cancer by quercetin [92]. Seo et al., also showed quercetin induces p-53 dependent apoptotic cell death in ERalpha-negative breast cancer cells [93]. Conversely, quercetin can induce p-53 independent apoptotic pathway in HT-29 colon cancer cells via AMPK/p38 signaling pathway [94]. Although various studies have shown the apoptotic activity of quercetin, there is further need to understand more detail about the mode of action and mechanisms responsible for quercetin induced apoptosis. Some of the quercetin induced anticancer effects in different cell lines are summarized in Table 1.
Table 1. Effects of quercetin on cancer types and cell signaling involved.
Table 1. Effects of quercetin on cancer types and cell signaling involved.
Organ/TissueCarcinogen/Cancer Cell LneMode of Study/Model SystemEffect/Signaling MechanismRef.
BreastMCF-7 breast cancer cellsIn vitroInduce antiproliferative effect and apoptosis by increased Bcl-2 and decreased Bax expression[95]
HCC1937 breast cancer cellsIn vitroInduce antiproliferative effect via PI3K-Akt/PKB pathway[76]
SK-Br3 breast cancer cellsIn vitroGrowth inhibition by decreasing level of Her-2/neu protein and inhibition of PI3K-Akt signaling pathway[77]
SK-Br3 breast cancer cellsIn vitroInduce antiproliferative effect by suppressing hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation and reduced vascular endothelial growth factor (VEGF) secretion[96]
4T1 breast cancer cellsIn vitroInduce antiproliferative effect and apoptosis by regulating Wnt/β-catenin signaling pathway[21]
TPA-treated MCF-7 breast cancer cellsIn vitroPrevents metastasis by inhibiting TPA-induced PKC δ/ERK/AP-1-dependent matrix metalloproteinase-9 activation and migration [86]
MDA-MB-231 breast cancer cellsIn vitroGrowth inhibition by arresting cell cycle and inducing and inducing apoptosis by regulating mitochondrial- and caspase-3-dependent pathways[91]
MCF-7 and MDA-MB-231 breast cancer cellsIn vitroinduces apoptosis through suppression of Twist via p38MAPK pathway[97]
ERalpha-negative breast cancer cellsIn vitroInduce antiproliferative effect and apoptosis via p53-dependent pathway[93]
PancreasMIA PaCa-2 and BxPC-3 pancreatic cancer cellsIn vitro and in vivo (nude mouse model)Induce antiproliferative effect and apoptosis. Inhibits tumor growth[74]
ColonCX-1 colon cancer cellsIn vitroInduce antiproliferative effect by suppressing hypoxia-inducible factor-1α (HIF-1α) accumulation and reduced vascular endothelial growth factor (VEGF) secretion[96]
SW480 colon cancer cellsIn vitroGrowth inhibition via inhibiting cyclin D(1) and survivin expression as well regulating Wnt/β-catenin signaling pathway[20]
HT-29 and HCT116 colon cancer cellsIn vitroregulates the sestrin 2-AMPK-p38 MAPK signaling pathway and inducing apoptosis via increasing the generation of intracellular ROS in a p53-independent manner[94]
HT-29 colon cancer cellsIn vitro and in vivo (male nude mice)Induces apoptosis via AMPK signaling pathway and reduce tumor volume [92]
ProstateLNCaP prostate cancer cellsIn vitroInduce antiproliferative effect by suppressing hypoxia-inducible factor-1α (HIF-1α) accumulation and reduced vascular endothelial growth factor (VEGF) secretion[96]
Chemically induced prostate cancerIn vivo (Sprague-Dawley male rats)Suppress tumor progression by inhibiting the EGFR signaling pathway, regulating cell adhesion molecules and decreased snail, slug, and twist mRNA levels[79]
PC-3 prostate cancer cellsIn vitroPrevent metastasis via regulating EGFR/PI3k/Akt/ERK1/2 pathway and by suppressing transcriptional repressors Snail, Slug and Twist[98]
LiverHepG2 hepatic cancer cellsIn vitroInduce antiproliferative effect by downregulating phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) via induction of p53[71]
HepG2 hepatic cancer cellsIn vitroInduce growth inhibition by cell cycle arrest at G1 phase and increasing levels of Cdk inhibitors p21 and p27 and tumor suppressor p53[80]
Lymphatic systemDalton’s lymphoma ascite cell lineIn vivoInhibiting cancer growth by down-regulation of PI3K-Akt1-p53 pathway and glycolytic metabolism[78]
Dalton’s lymphoma ascite cell lineIn vivoInduction of apoptosis and modulation of PKC signaling with the reduction of oxidative stress[99]
Salivary glandsACC salivary cancer cellsIn vitroInduce antiproliferative effect and apoptosis by down-regulating the PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway.[100]
OvarySKOV3 oarian cancer cellsIn vitroInhibiting cell growth by decreasing cyclin D1 expression level linked to alterations in G1/S phase[83]
SKOV3 oariancancer cellsIn vitro and in vivo (SKOV-3 xenograft mice model)Inducing apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via ROS mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway[101]
BoneU2OS osteocarcoma cellsIn vitroInhibiting cell growth by decreasing cyclin D1 expression level linked to alterations in G1/S phase[83]
CervixHeLa cervical cancer cellsIn vitroInduce cell growth inhibition and mitochondria mediated apoptosis via p53 induction and NF-kappaB inhibition[81]
HeLa cervical cancer cellsIn vitroInduce antiproliferative effect and apoptosis by promoting cytochrome release, ROS accumulation and inhibiting anti-apoptotic AKT and Bcl-2 expression. Also perform cell arrest at G2/M phase[102]
LungA549 lung cancer cellsIn vitroquercetin-3-glucuronide and quercetin-3'-sulfate enriched plasma induces cell growth inhibition by cell cycle arrest at the G (2)/M phase via downregulating cdk1 and cyclin B expression[82]
SkinJB6 P+ mouse epidermal cancer cellsIn vitroinhibit TNF-alpha-induced upregulation of MMP-9 and cell migration via p13K/Akt signaling pathway[87]
BrainU87 and U251 glioma cellsIn vitro/in vivo (C6 glioma xenograft models)Induce anti proliferative effect and autophagy[103]
U373MG glioblastoma cellsIn vitroInduce cell growth inhibition through mitochondria mediated apoptosis via activating Caspase-, caspase-7, JNK and p53 level. showed cell cycle arrest at sub-G1 phase[104]

5. Enhancing Bioavailability and Bioactivity of Quercetin Using Nanoparticles and Its Application in Cancer Treatment and Diagnosis

Although, quercetin has been studied as a potential candidate for cancer treatment it has certain limitations. Some of these limitations are illustrated in Figure 3. Hence, to overcome the restrictions offered by phytochemicals, one of the widely explored method is to deliver them through polymers, liposomes, chitosan and other drug carriers. These delivery carriers are used for enhancing their solubility in water, absorption in body, circulation time and target specificity. Some of the biodegradable materials commonly used for this purpose are discussed below.
Figure 3. Limitations of quercetin as an anti-cancer drug.
Figure 3. Limitations of quercetin as an anti-cancer drug.
Molecules 21 00108 g003

5.1. Silica Nanoparticles

The use of mesoporous silica nanoparticles as a promising drug delivery system has been reported in various studies due to its low in vivo toxicity [105], high stability and ability to be functionalized by various ligands to achieve targeted drug delivery [106,107,108]. In addition, mesoporous silica nanoparticles have high surface area and ordered tunable porosity rendering them high drug loading efficiency with better release kinetics [109,110]. The reported bio-distribution and excretion profile of mesoporous silica nanoparticles makes them an opportunistic nanomaterial for controlled drug delivery [111,112]. Zhang et al., showed increased oral bioavailability, ~154% compared to free poorly water soluble drug, by loading them onto mesoporous silica nanoparticles [113]. Physical adsorption and solvent evaporation are the most employed silica nanoparticles based drug loading methods [114,115]. Furthermore, Catauro et al. reported the sol-gel synthesis method of silica-quercetin hybrid material to counteract peri-implant diseases, in which the C-ring of quercetin was modified structurally while the O-catechol ring was intact to perform antioxidant activity [116]. As discussed earlier that the antioxidant property of quercetin provides it a better therapeutic potential against cancer, similar kind of silica-quercetin hybrid which retains their antioxidant property can be suggested as a potent anticancer agent. Additionally, aminopropyl functionalized mesoporous silica nanoparticles loaded with quercetin were also synthesized for topical application as a chemopreventive agent [117].
Based on the structure, another type of silica nanoparticles are silicon dioxide (SiO2) nanoparticles having smaller surface area compared to mesoporous silica nanoparticles. They are mainly employed to immobilize the therapeutic molecules to modulate their controlled release and thus enhancing their biological activities [118]. In 2011, US Food and Drug Administration (FDA) approved silica nanoparticles for first human clinical trial aimed at targeted imaging of cancer, reflecting the clinical acceptance of silica nanoparticles in near future [119,120]. Although the advances in silica based quercetin delivery system are rousing there are overwhelming tasks for its clinical application which still need to be solved. For example, there is a need for monitored bioimaging to understand the function of delivery system more precisely. This may assist in improving their efficiency of more controlled quercetin release in biological systems. Furthermore, toxicity investigation of silica-based drug delivery systems for quercetin is also a prerequisite. Thus, a more refined and successful strategy for silica-based quercetin delivery system may be expected in future, utilizing the benefits offered by the silica nanoparticles against cancer.

5.2. PLGA and PLA Nanoparticles

Poly lactic-co-glycolic acid (PLGA) and poly(d,l-lactic acid) (PLA) are FDA and European Medicine Agency (EMA) approved biodegradable polymers which first get hydrolyzed into lactic and glycolic acids and finally metabolized to CO2 and H2O via the Krebs cycle [121]. Attributed to their biocompatibility, these polymers have been immensely used for the preparation of drug loaded nanoparticles for the treatment of various diseases. The physicochemical properties of these polymers have been amended by synthesizing their various derivatives and co-polymers. Synthesized derivatives have varying molecular weights with diverse properties like modulated size, drug loading ability, controlled drug release, nanoparticle uptake efficiency, bio-distribution and circulating half-life of the nanodrug composites [122,123,124]. In numerous studies, anti-cancer agents have been encapsulated within PLGA nanoparticles and have shown significant improvement in drug uptake and cancer growth suppression. For example, significant enhancement in A549 cell (a human lung adenocarcinoma epithelial cell line) cytotoxicity was observed by quercetin encapsulated PLGA nanoparticles in combination with etopside-loaded PLGA nanoparticles, as compared to free drugs [125]. Similarly, approximately 50% (in 2 days) and 40% (in 5 days) reduction of breast cancer cells was reported upon treatment with free quercetin and PLA-quercetin, respectively, showing sustained release of drug by PLA-quercetin nanoparticles [126]. A study by Pool et al. demonstrated the presence of hydrogen bonds between quercetin molecules and PLGA [127]. They also revealed that increased drug release occurs in acidic pH, suggesting augmented expulsion of drug in tumor environment. Quercetin-gold loaded PLGA nanoparticles were found to display anti-proliferative activity on HepG2 hepatocarcinoma cells by interacting with cellular DNA and reducing deactylation of histone proteins, arresting the cell growth in the sub-G stage [128]. Orally delivered quercetin, co-encapsulated with tamoxifen, in PLGA polymeric nanoparticles significantly enhanced its bioavailability and suppressed breast cancer growth by inducing apoptosis [129]. In addition, there was no observed hepatotoxicity or oxidative stress compared to free drugs. In another study, quercetin loaded PEGylated PLGA nanoparticles, labeled with folic acid, were intravenously treated to human ovarian adenocarcinoma cells (IGROV-1) and human epithelial cells (HeLa) xenograft models. Researchers observed enhanced uptake of folic acid conjugated nanoparticles by selective tumor cells and suggested their future application in targeted drug delivery [130]. Besides, oral and intravenous delivery of quercetin loaded PLGA nanoparticles, peri-tumoral mode of injection was also reported in4T1 breast cancer xenograft mice model. The study demonstrated effective suppression of tumor growth by quercetin loaded PLGA nanoparticles, compared to control [131]. In addition to chemical synthesis of quercetin loaded PLA nanoparticles, greener approach for PLA nanoparticles synthesis for slow and sustained release of quercetin has also been explored [132]. Despite the fact that PLGA and PLA nanoparticles have shown appreciable advancements in drug delivery, there are noteworthy challenges which need to be addressed. Organic solvents used for the synthesis of PLGA/PLA nanoparticles are always challenging in respect to their complete removal, toxicity and emulsification method. Preparation of PLGA/PLA nanoparticles often requires bulk amount of aqueous phase for initial emulsification of polymeric dispersed phase creating a limitation for large scale production. Additionally, it may also cause variations in size range due to uneven emulsion droplet and PLGA/PLA precipitation. Furthermore, poor quercetin loading is also an issue to be solved. Therefore, there is a need for developing appropriate and convenient technologies to overcome the above mentioned challenges and to produce desired quercetin delivery system. In prospect, these nanoparticles can also be a promising therapeutic candidate for anticancer treatment.

5.3. Chitosan Nanoparticles

Chitosan, a natural polycationic polysaccharide, is an N-deacetylated derivative of chitin consisting of linear repeating units of 2-acetamido-2-deoxy-d-glucose and β-(1-4)-2-amino-2-deoxy-d-glucose [133]. Owing to the presence of surface amine groups and the modulatory effects on cellular F-actin, tight junction protein ZO-1 and protein kinase C, chitosan is rapidly internalized by cells and is considered an absorption enhancer [134,135,136]. Therefore, it is an attractive candidate for biomedical applications including tissue engineering, drug delivery, wound dressings and antimicrobial activity. As previously reported, chitosan possess anti-inflammatory and antioxidant properties [137,138]. In addition, it also serves as a biocompatible and biodegradable polymer [139]. Being polycationic, chitosan can interact with negatively charged molecules and can form a core shell nanostructure that serves as an efficient drug delivery system [140]. As a drug carrier, chitosan has been reported to be capable of delivering drugs to various organs such as kidney, liver, lungs and colon [141]. A pH sensitive, chitosan-coated nanoparticle system to enhance the oral uptake of drugs via chitosan mediated tight junction opening has also been developed [142]. Moreover, a complex delivery system made up of chitosan and its derivative (O-carboxymethylchitosan) has also been synthesized to enhance drug absorption through small intestine involving clathrin-mediated endocytosis [143]. David et al., reported the dose dependent anticancer activity of quercetin-loaded chitosan nanoparticles with and without 5-flourouracil against pancreatic cancer and gave a new insight for the application of quercetin-loaded chitosan nanoparticles for cancer treatment [144]. Interestingly, they also observed low toxicity of dual drug-loaded chitosan nanoparticles against normal L292 cells (murine aneuploidy fibrosarcoma cell line). Their cell internalization study showed the accumulation of dual drug-loaded chitosan nanoparticles in the interior of the cells within 4 h of treatment. Besides anti-proliferative activity, quercetin can also enhance the oral bioavailability of commercially available anticancer drugs such as paclitaxel by inhibiting MDR family members (P-gp, MRP1 and BCRP) and CYP3A subfamily of P-450 cytochrome which can metabolize paclitaxel [145]. Therefore, Wang et al., designed chitosan conjugated quercetin nanoparticles loaded with paclitaxel to enhance oral bioavailability and water solubility via circumventing P-gp efflux pumps [146]. While great advancements have been attained in the development of chitosan-based quercetin delivery system, some issues still need to be fixed before its clinical translation. Majorly, the biocompatibility of modified chitosan derivatives, used as quercetin carriers, should be explored in more detail. Additionally, the absorption and bioavailability of quercetin carried by chitosan or its derivatives can be further improved.

5.4. Liposomes

Liposomes consist of amphiphilic lipid molecules which can form a bilayer membrane spherical vesicle, well known to carry therapeutic and diagnostic cargos to their site of action [147,148]. Liposomes extravagate through the pores present in the capillary endothelium, found especially in tumor cells, and accumulate at the tumor sites [149]. Because of the presence of a lipid bilayer and an aqueous core, liposomes are capable of carrying and transporting both hydrophobic and hydrophilic therapeutic agents [150]. The physicochemical properties of liposomes such as size, surface charge, composition and targeting ligand can be modulated according to the drug, site of action and the disease, making it feasible for controlled and specific delivery system [151]. With the help of targeted drug delivery, liposomes have been employed to deliver low doses of drugs with reduced toxicity and side effects. Wang et al., reported enhanced cytotoxic effect of quercetin-loaded liposomes in C6 glioma cells. Additionally, they concluded the involvement of necrosis, rather than apoptosis, during tumor cell death [152]. Increased bioavailability, cellular uptake and aqueous solubility of quercetin loaded nanoliposomes were also reported using MCF-7 human breast cancer cells. Their data suggested the use of quercetin-loaded liposomes as an efficient antioxidant [153]. Recently, Soluplus micelles, an amphiphilic polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer, have been proposed to encapsulate poorly water soluble drugs for efficient bioavailability [154]. The study reported enhanced oral bioavailability of quercetin in beagle dogs after oral administration of quercetin-loaded polymeric micelles (relatively 286% more oral bioavailability compared to free quercetin). However, liposomes have certain limitations as a drug carrier including low drug loading, less stability, high cost and active targeting. This necessitates further research in designing innovative routes and methods for developing potent quercetin liposomal formulations as an anticancer agent.

5.5. Other Nanoparticles

To improve the efficacy of orally administered quercetin, Tan et al., employed polyethylene glycol (PEG)-derivatized phosphatidyl ethanolamine (PE) as a block copolymer for the synthesis of quercetin nanomicelles [155]. They further evaluated the interaction of nanomicelles with Caco-2 cells and studied their anti-proliferative effect on A549 lung cancer cells and a mice xenograft model. Quercetin nanomicellar solution exhibited suppressive tumor growth with a margin of 1.5 fold higher than free quercetin, displaying no observed toxicity in relevance to weight loss [155]. A novel approach to enhance the solubility of quercetin by fabricating quercetin nanoribbons by atmospheric pressure physical vapor deposition (PVD) approach has also been successfully attempted. The increased growth inhibitory effect of quercetin nanoribbons on 4T1 breast cancer cells also demonstrated their improved aqueous solubility and drug release profile [156]. Nevertheless, further studies are still required to understand the underlying mechanism of anticancer activity of these quercetin nanoformulations.

6. Future Perspectives and Limitations

The pharmacological effect of quercetin loaded/conjugated nanoparticles majorly depends on the drug carriers used and the physico-chemical properties of the nanoparticulate system. These characteristics can increase the stability of quercetin, its bioavailability and target specificity. Hence, an overview of the physicochemical properties and biological efficacy of some of the discussed nanoparticles are detailed in Table 2. Despite numerous in vitro and in vivo anti-cancer studies of quercetin nanoformulations, there are still some limitations for their clinical translation such as cost, safety and side effects [157]. The in vivo anticancer potential of quercetin nanoparticles have been evaluated on various kinds of cancer models among which oral administration is the most preferred route for quercetin nanoformulation administration [158]. Although various quercetin nanoparticles capable of enhancing quercetin bioavailability in the body have been synthesized, the need for more stable and target specific nanoparticles is still a challenging issue [159].
Also, a reduction in the side effects and toxicity of quercetin nanoparticles should be considered before they are applied for clinical purposes [160]. This can be achieved by the addition of cancer cell specific targeting moieties on the nanoparticles. It will not only enhance target specific delivery of nanoformulations but will also reduce their interaction with the normal cells, preventing any side effects of anticancerous drugs. Additionally, more controlled synthesis of nanoformulations will be required to fulfill the safety criteria specified by government authorities [161]. Furthermore, before entering the market as therapeutic agent, cost effectiveness of the nanoformulations will be a major issue and cheaper and affordable drugs are required.

7. Conclusions

Multifunctional quercetin, a dietary flavonoid, is a competent antioxidant and can serve as a potent anti-cancer agent. However, its efficiency as a therapeutic drug is low due to its rapid metabolism in the body. Thus, the use of biodegradable and biocompatible carriers as delivery systems can enhance the therapeutic competence of quercetin. Some of the most well-studied and available quercetin delivery systems are based on liposomes, PLGA, PLA, chitosan and silica. Both in vivo and in vitro studies have highlighted the anti-proliferative effect of quercetin-loaded nanoparticles on various types of cancer cells. However, the use of such nanoparticles at a clinical level still needs more process optimization to enhance their specificity and efficacy for their efficient clinical translation.
Table 2. The physico-chemical properties and anti-cancer effects of quercetin based nanoparticle systems.
Table 2. The physico-chemical properties and anti-cancer effects of quercetin based nanoparticle systems.
Delivery SystemCancer TypeChemicals/Polymer UsedSize (d) nmPDIEntrapment EfficiencyIn Vitro/In VivoEffective DoseEffectRef.
SilicaJR8 human melanoma cell lineaminopropyl functionalized mesoporous silica nanoparticle250 ± 50NANAIn vitro60 µM~50% inhibition of cell proliferation at 72 h[117]
Ex vivo (Porcine skin)0.27% w/w of quercetin in water/oil emulsion systemHigher amount of quercetin was retained in the skin as compared to control at 24 h
PLGA/PLAA549 human lung adenocarcinoma epithelial cell linePLGA (combination treatment of quercetin and etopside)153.4 ± 4.2 (etopside), 148.6 ± 1.6 (quercetin)0.058 ± 0.02 (etopside), 0.088 ± 0.03 (quercetin)63.88% ± 1.5% (etopside), 41.36% ± 3.4% (quercetin)In vitro50 µMEnhanced cytotoxic effect compared to free drugs combination at 72 h[125]
MDA-MB231 human breast cancer cell linePLA46 ± 6NA62% ± 3%In vitro100 µg/mL~40% decrease in cell viability in 5 days[126]
DMBA induced Breast cancerPLGA (coencapsulated quercetin and tamoxifen)185.3 ± 1.200.184 ± 0.00467.16% ± 1.24% (tamoxifen), 68.60% ± 1.58% (quercetin)In vitro10 µg/mLincrease in cell cytotoxicity[129]
In vivo (female SD rats)45 mg/kg (Oral, one time per week for 3 weeksTumor was reduced to ~32.36% after 30 days
HeLa cervical-tumor-derived cell line or IGROV-1 human ovarian carcinoma cell linePEG-PLGA and Folic acid as targeting ligand155.0 ± 1.2<0.297.8 ± 0.14In vitro10 µM~56.63% reduction in cell viability of HeLa[130]
In vivo (female athymic nude and SHrN mice xenograft model)250 μL of 50 mg polymer/mL (single intravenous injection)Folic acid enhances selective uptake of nanoparticles by folate receptor enriched cancer cells
MDA-MB-231 human breast cancer cell line and 4T1 murine mammary cancer cell lineMPEG-PLA155.3 ± 3.20.2 ± 0.05NAIn vitro13.5 µg/mL~38% lower cell viability compared to control[131]
In vivo (female BALB/c mouse xenograft model)0.5 mg/kg (peritumoral injection, every third day till day 19)Reduced tumor size as compared to control
ChitosanMiaPaCa2, Pancreatic cancer cell lineChitosan300NA91%In vitro10 µM to 100µMDose dependent cell inhibition[144]
MiaPaCa2, Pancreatic cancer cell lineChitosan (quercetin and 5-flourouracil dual drug loading)400NA95% (quercetin), 75% (flourouracil)In vitro39.7 µM (quercetin) and 75 µM (flourouracil)~70% decrease in cell viability[144]
HepG2 human liver cancer cell lineChirosan-quercetin conjugate loaded with paclitaxel185.8 ± 4.60.134 ± 0.05685.63% ± 1.26%In vitro0.01–100 µg/mLDose dependent cytotoxic effect with IC50 0.11 µg/mL[146]
In vivo (male ICR xenograft models)20 mg/kg (single oral dose)~71.22% reduction in tumor size
LiposomesC6 glioma cell lineglyceryl behenate, soy lecithin, and cholesterol116.7NANAIn vitro0–400 μMInduced necrotic cell death[152]
MCF-7 human breast cancer cell linePhosphotidyl choline100.974 ± 0.3NA40.7% ± 3.1%In vitro50 mM/mL~83% inhibition in cell proliferation at 48 h[153]
MCF-7 and MDA-MB-231 human breast cancer cell lineSoy lecithin, glyceryl tridecanoate, glyceryl tripalmitate, vitamin E acetate, Kolliphor HS15320.05995%In vitro50 µM~13.7% reduction in viability of MCF-7 cells and ~13.4% reduction in viability of MDA-MB-231 cells at 48 h[162]
NanomicellesA549 human lung cancer cell lineDSPE-PEG2000 Nanomicelles15.4–18.5<0.250≥88.9%In vitro100 µMDecreased cell viability at 72 h[155]
In vivo (female Rag-2M mice xenograft Model)30 mg/kg (three times per week for 3 weeks, perorally)~1.5 fold higher tumor growth inhibition than free quercetin control group
Nanoribbon4T1 murine mammary cancer cell lineNanoribbon fabricated by atmospheric pressure PVD100–200NANAIn vitroNA~57% reduction in cell viability[156]
NA: not available; PDI: poly dispersity index; d: diameter.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2055560 & 2014R1A1A4A03009388), and by Hallym University Research Fund.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Xiao, Z.P.; Peng, Z.Y.; Peng, M.J.; Yan, W.B.; Ouyang, Y.Z.; Zhu, H.L. Flavonoids health benefits and their molecular mechanism. Mini-Rev. Med. Chem. 2011, 11, 169–177. [Google Scholar] [CrossRef] [PubMed]
  2. Haddad, A.Q.; Fleshner, N.; Nelson, C.; Saour, B.; Musquera, M.; Venkateswaran, V.; Klotz, L. Antiproliferative mechanisms of the flavonoids 2,2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr. Cancer 2010, 62, 668–681. [Google Scholar] [CrossRef] [PubMed]
  3. Formica, J.V.; Regelson, W. Review of the biology of Quercetin and related bioflavonoids. Food Chem. Toxicol. 1995, 33, 1061–1080. [Google Scholar] [CrossRef]
  4. Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013, 2013. [Google Scholar] [CrossRef] [PubMed]
  5. Moon, J.H.; Tsushida, T.; Nakahara, K.; Terao, J. Identification of quercetin 3-O-β-d-glucuronide as an antioxidative metabolite in rat plasma after oral administration of quercetin. Free Radic. Biol. Med. 2001, 30, 1274–1285. [Google Scholar] [CrossRef]
  6. Bors, W.; Michel, C.; Saran, M. Flavonoid antioxidants: Rate constants for reactions with oxygen radicals. Methods Enzymol. 1994, 234, 420–429. [Google Scholar] [PubMed]
  7. Prior, R.L. Fruits and vegetables in the prevention of cellular oxidative damage. Am. J. Clin. Nutr. 2003, 78, 570S–578S. [Google Scholar] [PubMed]
  8. Erkoç, Ş.; Erkoç, F.; Keskin, N. Theoretical investigation of quercetin and its radical isomers. J. Mol. Struct. THEOCHEM 2003, 631, 141–146. [Google Scholar] [CrossRef]
  9. Kampa, M.; Hatzoglou, A.; Notas, G.; Damianaki, A.; Bakogeorgou, E.; Gemetzi, C.; Kouroumalis, E.; Martin, P.-M.; Castanas, E. Wine antioxidant polyphenols inhibit the proliferation of human prostate cancer cell lines. Nutr. Cancer 2000, 37, 223–233. [Google Scholar] [CrossRef] [PubMed]
  10. American Cancer Society. Cancer Facts and Figures 2015; American Cancer Society: Atlanta, GA, USA, 2015. [Google Scholar]
  11. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 2015, 65, 5–29. [Google Scholar] [CrossRef] [PubMed]
  12. Donaldson, M.S. Nutrition and cancer: A review of the evidence for an anti-cancer diet. Nutr. J. 2004, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Riboli, E.; Norat, T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. Am. J. Clin. Nutr. 2003, 78, 559S–569S. [Google Scholar] [PubMed]
  14. Nabavi, S.F.; Daglia, M.; Moghaddam, A.H.; Habtemariam, S.; Nabavi, S.M. Curcumin and liver disease: from chemistry to medicine. Compr. Rev. Food Sci. Food Saf. 2014, 13, 62–77. [Google Scholar] [CrossRef]
  15. Lee, K.W.; Bode, A.M.; Dong, Z. Molecular targets of phytochemicals for cancer prevention. Nat. Rev. Cancer 2011, 11, 211–218. [Google Scholar] [CrossRef] [PubMed]
  16. Goodman, M.; Bostick, R.M.; Kucuk, O.; Jones, D.P. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radic. Biol. Med. 2011, 51, 1068–1084. [Google Scholar] [CrossRef] [PubMed]
  17. Shu, L.; Cheung, K.L.; Khor, T.O.; Chen, C.; Kong, A.N. Phytochemicals: Cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev. 2010, 29, 483–502. [Google Scholar] [CrossRef] [PubMed]
  18. Bishayee, A. Cancer prevention and treatment with resveratrol: From rodent studies to clinical trials. Cancer Prev. Res. 2009, 2, 409–418. [Google Scholar] [CrossRef] [PubMed]
  19. Yuan, Z.; Long, C.; Junming, T.; Qihuan, L.; Youshun, Z.; Chan, Z. Quercetin-induced apoptosis of HL-60 cells by reducing PI3K/Akt. Mol. Biol. Rep. 2012, 39, 7785–7793. [Google Scholar] [CrossRef] [PubMed]
  20. Shan, B.E.; Wang, M.X.; Li, R.Q. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/β-catenin signaling pathway. Cancer Investig. 2009, 27, 604–612. [Google Scholar] [CrossRef] [PubMed]
  21. Kim, H.; Seo, E.M.; Sharma, A.R.; Ganbold, B.; Park, J.; Sharma, G.; Kang, Y.H.; Song, D.K.; Lee, S.S.; Nam, J.S. Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells. Int. J. Oncol. 2013, 43, 1319–1325. [Google Scholar] [PubMed]
  22. Huang, Y.T.; Hwang, J.J.; Lee, P.P.; Ke, F.C.; Huang, J.H.; Huang, C.J.; Kandaswami, C.; Middleton, E.; Lee, M.T. Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br. J. Pharmacol. 1999, 128, 999–1010. [Google Scholar] [CrossRef] [PubMed]
  23. Cai, X.; Fang, Z.; Dou, J.; Yu, A.; Zhai, G. Bioavailability of quercetin: Problems and promises. Curr. Med. Chem. 2013, 20, 2572–2582. [Google Scholar] [CrossRef] [PubMed]
  24. Khushnud, T.; Mousa, S.A. Potential role of naturally derived polyphenols and their nanotechnology delivery in cancer. Mol. Biotechnol. 2013, 55, 78–86. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, S.; Zhang, J.; Chen, M.; Wang, Y. Delivering flavonoids into solid tumors using nanotechnologies. Expert Opin. Drug Deliv. 2013, 10, 1411–1428. [Google Scholar] [CrossRef] [PubMed]
  26. Ferry, D.R.; Smith, A.; Malkhandi, J.; Fyfe, D.W.; deTakats, P.G.; Anderson, D.; Baker, J.; Kerr, D.J. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer. Res. 1996, 2, 659–668. [Google Scholar] [PubMed]
  27. Mukerjee, A.; Vishwanatha, J.K. Formulation, characterization and evaluation of curcumin-loaded PLGA nanospheres for cancer therapy. Anticancer Res. 2009, 29, 3867–3875. [Google Scholar] [PubMed]
  28. Jeetah, R.; Bhaw-Luximon, A.; Jhurry, D. Nanopharmaceutics: Phytochemical-based controlled or sustained drug-delivery systems for cancer treatment. J. Biomed. Nanotechnol. 2014, 10, 1810–1840. [Google Scholar] [CrossRef] [PubMed]
  29. Sharma, A.R.; Kundu, S.K.; Nam, J.S.; Sharma, G.; Priya Doss, C.G.; Lee, S.S.; Chakraborty, C. Next generation delivery system for proteins and genes of therapeutic purpose: Why and how? Biomed. Res. Int. 2014, 2014, 327950. [Google Scholar] [CrossRef] [PubMed]
  30. Sharma, G.; Sharma, A.R.; Nam, J.S.; Doss, G.P.; Lee, S.S.; Chakraborty, C. Nanoparticle based insulin delivery system: The next generation efficient therapy for Type 1 diabetes. J. Nanobiotechnol. 2015, 13, 74. [Google Scholar] [CrossRef] [PubMed]
  31. Mulik, R.S.; Monkkonen, J.; Juvonen, R.O.; Mahadik, K.R.; Paradkar, A.R. Apoptosis-induced anticancer effect of transferrin-conjugated solid lipid nanoparticles of curcumin. Cancer Nanotechnol. 2012, 3, 65–81. [Google Scholar] [CrossRef] [PubMed]
  32. Morand, C.; Crespy, V.; Manach, C.; Besson, C.; Demigne, C.; Remesy, C. Plasma metabolites of quercetin and their antioxidant properties. Am. J. Physiol. 1998, 275, R212–R219. [Google Scholar] [PubMed]
  33. Cornard, J.P.; Dangleterre, L.; Lapouge, C. Computational and spectroscopic characterization of the molecular and electronic structure of the Pb(II)-quercetin complex. J. Phys. Chem. A 2005, 109, 10044–10051. [Google Scholar] [CrossRef] [PubMed]
  34. Mendoza-Wilson, A.M.A.; Glossman-Mitnik, D. CHIH-DFT determination of the molecular structure, infrared and ultraviolet spectra of the flavonoid quercetin. J. Mol. Str. THEOCHEM 2004, 681, 71–76. [Google Scholar] [CrossRef]
  35. Fischer, C.; Speth, V.; Fleig-Eberenz, S.; Neuhaus, G. Induction of zygotic polyembryos in wheat: Influence of auxin polar transport. Plant Cell 1997, 9, 1767–1780. [Google Scholar] [CrossRef] [PubMed]
  36. Williams, C.A.; Grayer, R.J. Anthocyanins and other flavonoids. Nat. Prod. Rep. 2004, 21, 539–573. [Google Scholar] [CrossRef] [PubMed]
  37. Harborne, J.B.; Williams, C.A. Advances in flavonoid research since 1992. Phytochemistry 2000, 55, 481–504. [Google Scholar] [CrossRef]
  38. Fang, N.; Yu, S.; Mabry, T.J. Flavonoids from Ageratina calophylla. Phytochemistry 1986, 25, 2684–2686. [Google Scholar] [CrossRef]
  39. Zeng, L.-M.; Wang, C.-J.; Su, J.-Y.; Li, D.; Owen, N.L.; Lu, Y.; Lu, N.; Zheng, Q.-T. Flavonoids from the red alga Acanthophora spicifera. Chin. J. Chem. 2001, 19, 1097–1100. [Google Scholar] [CrossRef]
  40. Dal Santo, S.; Tornielli, G.B.; Zenoni, S.; Fasoli, M.; Farina, L.; Anesi, A.; Guzzo, F.; Delledonne, M.; Pezzotti, M. The plasticity of the grapevine berry transcriptome. Genome Biol. 2013, 14. [Google Scholar] [CrossRef] [PubMed]
  41. Rice-Evans, C.; Miller, N.; Paganga, G. Antioxidant properties of phenolic compounds. Trends Plant Sci. 1997, 2, 152–159. [Google Scholar] [CrossRef]
  42. Heijnen, C.G.; Haenen, G.R.; Oostveen, R.M.; Stalpers, E.M.; Bast, A. Protection of flavonoids against lipid peroxidation: The structure activity relationship revisited. Free Radic. Res. 2002, 36, 575–581. [Google Scholar] [CrossRef] [PubMed]
  43. Liu, L.P.; Liao, Z.P.; Yin, D.; Li, W.D.; Liu, D.; Li, Q.; Huang, Q.R.; Yang, Y.F.; He, M. The protective effects of Polygonum multiflorum stilbene glycoside preconditioning in an ischemia/reperfusion model of HUVECs. Acta Pharmacol. Sin. 2010, 31, 405–412. [Google Scholar] [CrossRef] [PubMed]
  44. Zhu, Q.Y.; Huang, Y.; Chen, Z.Y. Interaction between flavonoids and alpha-tocopherol in human low density lipoprotein. J. Nutr. Biochem. 2000, 11, 14–21. [Google Scholar] [CrossRef]
  45. Borghetti, G.S.; Carini, J.P.; Honorato, S.B.; Ayala, A.P.; Moreira, J.C. F.; Bassani, V.L. Physicochemical properties and thermal stability of quercetin hydrates in the solid state. Thermochim. Acta 2012, 539, 109–114. [Google Scholar] [CrossRef]
  46. Ghosh, D.; Ghosh, S.; Sarkar, S.; Ghosh, A.; Das, N.; Das Saha, K.; Mandal, A.K. Quercetin in vesicular delivery systems: Evaluation in combating arsenic-induced acute liver toxicity associated gene expression in rat model. Chem. Biol. Interact. 2010, 186, 61–71. [Google Scholar] [CrossRef] [PubMed]
  47. Bischoff, S.C. Quercetin: Potentials in the prevention and therapy of disease. Curr. Opin. Clin. Nutr. Metab. Care 2008, 11, 733–740. [Google Scholar] [CrossRef] [PubMed]
  48. Harnly, J.M.; Doherty, R.F.; Beecher, G.R.; Holden, J.M.; Haytowitz, D.B.; Bhagwat, S.; Gebhardt, S. Flavonoid content of U.S. fruits, vegetables, and nuts. J. Agric. Food Chem. 2006, 54, 9966–9977. [Google Scholar] [CrossRef] [PubMed]
  49. Sampson, L.; Rimm, E.; Hollman, P.C.; de Vries, J.H.; Katan, M.B. Flavonol and flavone intakes in US health professionals. J. Am. Diet Assoc. 2002, 102, 1414–1420. [Google Scholar] [CrossRef]
  50. Brown, J.P. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat. Res. 1980, 75, 243–277. [Google Scholar] [CrossRef]
  51. Jones, E.; Hughes, R.E. Quercetin, flavonoids and the life-span of mice. Exp. Gerontol. 1982, 17, 213–217. [Google Scholar] [CrossRef]
  52. Johannot, L.; Somerset, S.M. Age-related variations in flavonoid intake and sources in the Australian population. Public Health Nutr. 2006, 9, 1045–1054. [Google Scholar] [CrossRef] [PubMed]
  53. Nishimuro, H.; Ohnishi, H.; Sato, M.; Ohnishi-Kameyama, M.; Matsunaga, I.; Naito, S.; Ippoushi, K.; Oike, H.; Nagata, T.; Akasaka, H.; et al. Estimated daily intake and seasonal food sources of quercetin in Japan. Nutrients 2015, 7, 2345–2358. [Google Scholar] [CrossRef] [PubMed]
  54. Jackson, M.J. The assessment of bioavailability of micronutrients: Introduction. Eur. J. Clin. Nutr. 1997, 51 (Suppl. 1), S1–S2. [Google Scholar] [PubMed]
  55. Tamura, G.; Gold, C.; Ferro-Luzzi, A.; Ames, B.N. Fecalase: A model for activation of dietary glycosides to mutagens by intestinal flora. Proc. Natl. Acad. Sci. USA 1980, 77, 4961–4965. [Google Scholar] [CrossRef] [PubMed]
  56. Crespy, V.; Morand, C.; Besson, C.; Manach, C.; Demigne, C.; Remesy, C. Quercetin, but not its glycosides, is absorbed from the rat stomach. J. Agric. Food Chem. 2002, 50, 618–621. [Google Scholar] [CrossRef] [PubMed]
  57. Crespy, V.; Morand, C.; Manach, C.; Besson, C.; Demigne, C.; Remesy, C. Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am. J. Physiol. 1999, 277, G120–G126. [Google Scholar] [PubMed]
  58. Nait Chabane, M.; al Ahmad, A.; Peluso, J.; Muller, C.D.; Ubeaud, G. Quercetin and naringenin transport across human intestinal Caco-2 cells. J. Pharm. Pharmacol. 2009, 61, 1473–1483. [Google Scholar] [CrossRef] [PubMed]
  59. Moon, J.H.; Nakata, R.; Oshima, S.; Inakuma, T.; Terao, J. Accumulation of quercetin conjugates in blood plasma after the short-term ingestion of onion by women. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2000, 279, R461–R467. [Google Scholar] [PubMed]
  60. Conquer, J.A.; Maiani, G.; Azzini, E.; Raguzzini, A.; Holub, B.J. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J. Nutr. 1998, 128, 593–597. [Google Scholar] [PubMed]
  61. Walle, T.; Walle, U.K.; Halushka, P.V. Carbon Dioxide Is the Major Metabolite of Quercetin in Humans. J. Nutr. 2001, 131, 2648–2652. [Google Scholar] [PubMed]
  62. Justino, G.C.; Santos, M.R.; Canario, S.; Borges, C.; Florencio, M.H.; Mira, L. Plasma quercetin metabolites: Structure-antioxidant activity relationships. Arch. Biochem. Biophys. 2004, 432, 109–121. [Google Scholar] [CrossRef] [PubMed]
  63. Mullen, W.; Rouanet, J.M.; Auger, C.; Teissedre, P.L.; Caldwell, S.T.; Hartley, R.C.; Lean, M.E.; Edwards, C.A.; Crozier, A. Bioavailability of [2-(14)C]quercetin-4′-glucoside in rats. J. Agric. Food Chem. 2008, 56, 12127–12137. [Google Scholar] [CrossRef] [PubMed]
  64. Hong, Y.J.; Mitchell, A.E. Metabolic profiling of flavonol metabolites in human urine by liquid chromatography and tandem mass spectrometry. J. Agric. Food Chem. 2004, 52, 6794–6801. [Google Scholar] [CrossRef] [PubMed]
  65. Okamoto, T. Safety of quercetin for clinical application (Review). Int. J. Mol. Med. 2005, 16, 275–278. [Google Scholar] [CrossRef] [PubMed]
  66. Crebelli, R.; Aquilina, G.; Falcone, E.; Carere, A. Urinary and faecal mutagenicity in Sprague-Dawley rats dosed with the food mutagens quercetin and rutin. Food Chem. Toxicol. 1987, 25, 9–15. [Google Scholar] [CrossRef]
  67. Harwood, M.; Danielewska-Nikiel, B.; Borzelleca, J.F.; Flamm, G.W.; Williams, G.M.; Lines, T.C. 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. Food Chem. Toxicol. 2007, 45, 2179–2205. [Google Scholar] [CrossRef] [PubMed]
  68. Suolinna, E.M.; Buchsbaum, R.N.; Racker, E. The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res. 1975, 35, 1865–1872. [Google Scholar] [PubMed]
  69. Hosokawa, N.; Hirayoshi, K.; Nakai, A.; Hosokawa, Y.; Marui, N.; Yoshida, M.; Sakai, T.; Nishino, H.; Aoike, A.; Kawai, K.; et al. Flavonoids inhibit the expression of heat shock proteins. Cell Struct. Funct. 1990, 15, 393–401. [Google Scholar] [CrossRef] [PubMed]
  70. Scambia, G.; Ranelletti, F.O.; Panici, P.B.; Piantelli, M.; Bonanno, G.; de Vincenzo, R.; Ferrandina, G.; Rumi, C.; Larocca, L.M.; Mancuso, S. Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells. Br. J. Cancer 1990, 62, 942–946. [Google Scholar] [CrossRef] [PubMed]
  71. Maurya, A.K.; Vinayak, M. Anticarcinogenic action of quercetin by downregulation of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) via induction of p53 in hepatocellular carcinoma (HepG2) cell line. Mol. Biol. Rep. 2015, 42, 1419–1429. [Google Scholar] [CrossRef] [PubMed]
  72. Yoshida, M.; Sakai, T.; Hosokawa, N.; Marui, N.; Matsumoto, K.; Fujioka, A.; Nishino, H.; Aoike, A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett. 1990, 260, 10–13. [Google Scholar] [CrossRef]
  73. Edwards, J.M.; Raffauf, R.F.; le Quesne, P.W. Antineoplastic activity and cytotoxicity of flavones, isoflavones, and flavanones. J. Nat. Prod. 1979, 42, 85–91. [Google Scholar] [CrossRef] [PubMed]
  74. Angst, E.; Park, J.L.; Moro, A.; Lu, Q.Y.; Lu, X.; Li, G.; King, J.; Chen, M.; Reber, H.A.; Go, V.L.; et al. The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo. Pancreas 2013, 42, 223–229. [Google Scholar] [CrossRef] [PubMed]
  75. Bruning, A. Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anticancer Agents Med. Chem. 2013, 13, 1025–1031. [Google Scholar] [CrossRef] [PubMed]
  76. Gulati, N.; Laudet, B.; Zohrabian, V.M.; Murali, R.; Jhanwar-Uniyal, M. The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res. 2006, 26, 1177–1181. [Google Scholar] [PubMed]
  77. Jeong, J.H.; An, J.Y.; Kwon, Y.T.; Li, L.Y.; Lee, Y.J. Quercetin-induced ubiquitination and down-regulation of Her-2/neu. J. Cell. Biochem. 2008, 105, 585–595. [Google Scholar] [CrossRef] [PubMed]
  78. Maurya, A.K.; Vinayak, M. Quercetin regresses Dalton’s lymphoma growth via suppression of PI3K/AKT signaling leading to upregulation of p53 and decrease in energy metabolism. Nutr. Cancer 2015, 67, 354–363. [Google Scholar] [CrossRef] [PubMed]
  79. Firdous, A.B.; Sharmila, G.; Balakrishnan, S.; RajaSingh, P.; Suganya, S.; Srinivasan, N.; Arunakaran, J. Quercetin, a natural dietary flavonoid, acts as a chemopreventive agent against prostate cancer in an in vivo model by inhibiting the EGFR signaling pathway. Food Funct. 2014, 5, 2632–2645. [Google Scholar] [CrossRef] [PubMed]
  80. Mu, C.; Jia, P.; Yan, Z.; Liu, X.; Li, X.; Liu, H. Quercetin induces cell cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods Find Exp. Clin. Pharmacol. 2007, 29, 179–183. [Google Scholar] [CrossRef] [PubMed]
  81. VidyaPriyadarsini, R.; SenthilMurugan, R.; Maitreyi, S.; Ramalingam, K.; Karunagaran, D.; Nagini, S. The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-kappaB inhibition. Eur. J. Pharmacol. 2010, 649, 84–91. [Google Scholar] [CrossRef] [PubMed]
  82. Yeh, S.L.; Yeh, C.L.; Chan, S.T.; Chuang, C.H. Plasma rich in quercetin metabolites induces G2/M arrest by upregulating PPAR-gamma expression in human A549 lung cancer cells. Planta Med. 2011, 77, 992–998. [Google Scholar] [CrossRef] [PubMed]
  83. Catanzaro, D.; Ragazzi, E.; Vianello, C.; Caparrotta, L.; Montopoli, M. Effect of Quercetin on Cell Cycle and Cyclin Expression in Ovarian Carcinoma and Osteosarcoma Cell Lines. Nat. Prod. Commun. 2015, 10, 1365–1368. [Google Scholar] [PubMed]
  84. Huang, C.Y.; Chan, C.Y.; Chou, I.T.; Lien, C.H.; Hung, H.C.; Lee, M.F. Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR-overexpressing oral cancer cells. J. Nutr. Biochem. 2013, 24, 1596–1603. [Google Scholar] [CrossRef] [PubMed]
  85. Liabakk, N.B.; Talbot, I.; Smith, R.A.; Wilkinson, K.; Balkwill, F. Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 1996, 56, 190–196. [Google Scholar] [PubMed]
  86. Lin, C.W.; Hou, W.C.; Shen, S.C.; Juan, S.H.; Ko, C.H.; Wang, L.M.; Chen, Y.C. Quercetin inhibition of tumor invasion via suppressing PKC δ/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 2008, 29, 1807–1815. [Google Scholar] [CrossRef] [PubMed]
  87. Hwang, M.K.; Song, N.R.; Kang, N.J.; Lee, K.W.; Lee, H.J. Activation of phosphatidylinositol 3-kinase is required for tumor necrosis factor-alpha-induced upregulation of matrix metalloproteinase-9: Its direct inhibition by quercetin. Int. J. Biochem. Cell Biol. 2009, 41, 1592–1600. [Google Scholar] [CrossRef] [PubMed]
  88. Lee, L.T.; Huang, Y.T.; Hwang, J.J.; Lee, A.Y.; Ke, F.C.; Huang, C.J.; Kandaswami, C.; Lee, P.P.; Lee, M.T. Transinactivation of the epidermal growth factor receptor tyrosine kinase and focal adhesion kinase phosphorylation by dietary flavonoids: Effect on invasive potential of human carcinoma cells. Biochem. Pharmacol. 2004, 67, 2103–2114. [Google Scholar] [CrossRef] [PubMed]
  89. Jacobson, M.D.; Weil, M.; Raff, M.C. Programmed cell death in animal development. Cell 1997, 88, 347–354. [Google Scholar] [CrossRef]
  90. Lowe, S.W.; Lin, A.W. Apoptosis in cancer. Carcinogenesis 2000, 21, 485–495. [Google Scholar] [CrossRef] [PubMed]
  91. Chien, S.Y.; Wu, Y.C.; Chung, J.G.; Yang, J.S.; Lu, H.F.; Tsou, M.F.; Wood, W.G.; Kuo, S.J.; Chen, D.R. Quercetin-induced apoptosis acts through mitochondrial- and caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells. Hum. Exp. Toxicol. 2009, 28, 493–503. [Google Scholar] [CrossRef] [PubMed]
  92. Kim, H.J.; Kim, S.K.; Kim, B.S.; Lee, S.H.; Park, Y.S.; Park, B.K.; Kim, S.J.; Kim, J.; Choi, C.; Kim, J.S.; et al. Apoptotic effect of quercetin on HT-29 colon cancer cells via the AMPK signaling pathway. J. Agric. Food Chem. 2010, 58, 8643–8650. [Google Scholar] [CrossRef] [PubMed]
  93. Seo, H.S.; Ju, J.H.; Jang, K.; Shin, I. Induction of apoptotic cell death by phytoestrogens by up-regulating the levels of phospho-p53 and p21 in normal and malignant estrogen receptor alpha-negative breast cells. Nutr. Res. 2011, 31, 139–146. [Google Scholar] [CrossRef] [PubMed]
  94. Kim, G.T.; Lee, S.H.; Kim, J.I.; Kim, Y.M. Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner. Int. J. Mol. Med. 2014, 33, 863–869. [Google Scholar] [CrossRef] [PubMed]
  95. Duo, J.; Ying, G.G.; Wang, G.W.; Zhang, L. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol. Med. Rep. 2012, 5, 1453–1456. [Google Scholar] [PubMed]
  96. Lee, D.H.; Lee, Y.J. Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis. J. Cell. Biochem. 2008, 105, 546–553. [Google Scholar] [CrossRef] [PubMed]
  97. Ranganathan, S.; Halagowder, D.; Sivasithambaram, N.D. Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells. PLoS ONE 2015, 10, e0141370. [Google Scholar] [CrossRef] [PubMed]
  98. Bhat, F.A.; Sharmila, G.; Balakrishnan, S.; Arunkumar, R.; Elumalai, P.; Suganya, S.; Raja Singh, P.; Srinivasan, N.; Arunakaran, J. Quercetin reverses EGF-induced epithelial to mesenchymal transition and invasiveness in prostate cancer (PC-3) cell line via EGFR/PI3K/Akt pathway. J. Nutr. Biochem. 2014, 25, 1132–1139. [Google Scholar] [CrossRef] [PubMed]
  99. Maurya, A.K.; Vinayak, M. Modulation of PKC signaling and induction of apoptosis through suppression of reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): Key role of quercetin in cancer prevention. Tumour Biol. 2015, 36, 8913–8924. [Google Scholar] [CrossRef] [PubMed]
  100. Sun, Z.J.; Chen, G.; Hu, X.; Zhang, W.; Liu, Y.; Zhu, L.X.; Zhou, Q.; Zhao, Y.F. Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma: Its inhibition by quercetin. Apoptosis 2010, 15, 850–863. [Google Scholar] [CrossRef] [PubMed]
  101. Yi, L.; Zongyuan, Y.; Cheng, G.; Lingyun, Z.; Guilian, Y.; Wei, G. Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway. Cancer Sci. 2014, 105, 520–527. [Google Scholar] [CrossRef] [PubMed]
  102. Bishayee, K.; Ghosh, S.; Mukherjee, A.; Sadhukhan, R.; Mondal, J.; Khuda-Bukhsh, A.R. Quercetin induces cytochrome-c release and ROS accumulation to promote apoptosis and arrest the cell cycle in G2/M, in cervical carcinoma: Signal cascade and drug-DNA interaction. Cell Prolif. 2013, 46, 153–163. [Google Scholar] [CrossRef] [PubMed]
  103. Bi, Y.; Shen, C.; Li, C.; Liu, Y.; Gao, D.; Shi, C.; Peng, F.; Liu, Z.; Zhao, B.; Zheng, Z.; et al. Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells. Tumour Biol. 2015. [Google Scholar] [CrossRef] [PubMed]
  104. Kim, H.; Moon, J.Y.; Ahn, K.S.; Cho, S.K. Quercetin induces mitochondrial mediated apoptosis and protective autophagy in human glioblastoma U373MG cells. Oxid. Med. Cell. Longev. 2013, 2013, 596496. [Google Scholar] [CrossRef] [PubMed]
  105. Hudson, S.P.; Padera, R.F.; Langer, R.; Kohane, D.S. The biocompatibility of mesoporous silicates. Biomaterials 2008, 29, 4045–4055. [Google Scholar] [CrossRef] [PubMed]
  106. Ambrogio, M.W.; Thomas, C.R.; Zhao, Y.L.; Zink, J.I.; Stoddart, J.F. Mechanized silica nanoparticles: A new frontier in theranostic nanomedicine. Acc. Chem. Res. 2011, 44, 903–913. [Google Scholar] [CrossRef] [PubMed]
  107. Fontecave, T.; Sanchez, C.; Azaïs, T.; Boissière, C. Chemical modification as a versatile tool for tuning stability of silica based mesoporous carriers in biologically relevant conditions. Chem. Mater. 2012, 24, 4326–4336. [Google Scholar] [CrossRef]
  108. Wang, Y.; Zhao, Q.; Han, N.; Bai, L.; Li, J.; Liu, J.; Che, E.; Hu, L.; Zhang, Q.; Jiang, T.; Wang, S. Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 313–327. [Google Scholar] [CrossRef] [PubMed]
  109. Andersson, J.; Rosenholm, J.; Areva, S.; Lindén, M. Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro- and mesoporous silica matrices. Chem. Mater. 2004, 16, 4160–4167. [Google Scholar] [CrossRef]
  110. Hu, Y.; Zhi, Z.; Zhao, Q.; Wu, C.; Zhao, P.; Jiang, H.; Jiang, T.; Wang, S. 3D cubic mesoporous silica microsphere as a carrier for poorly soluble drug carvedilol. Microporous Mesoporous Mater. 2012, 147, 94–101. [Google Scholar] [CrossRef]
  111. Souris, J.S.; Lee, C.H.; Cheng, S.H.; Chen, C.T.; Yang, C.S.; Ho, J.A.; Mou, C.Y.; Lo, L.W. Surface charge-mediated rapid hepatobiliary excretion of mesoporous silica nanoparticles. Biomaterials 2010, 31, 5564–5574. [Google Scholar] [CrossRef] [PubMed]
  112. Lu, J.; Liong, M.; Li, Z.; Zink, J.I.; Tamanoi, F. Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small 2010, 6, 1794–1805. [Google Scholar] [CrossRef] [PubMed]
  113. Zhang, Y.; Wang, J.; Bai, X.; Jiang, T.; Zhang, Q.; Wang, S. Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs. Mol. Pharm. 2012, 9, 505–513. [Google Scholar] [CrossRef] [PubMed]
  114. Ahern, R.J.; Hanrahan, J.P.; Tobin, J.M.; Ryan, K.B.; Crean, A.M. Comparison of fenofibrate-mesoporous silica drug-loading processes for enhanced drug delivery. Eur. J. Pharm. Sci. 2013, 50, 400–409. [Google Scholar] [CrossRef] [PubMed]
  115. Zhang, Y.; Jiang, T.; Zhang, Q.; Wang, S. Inclusion of telmisartan in mesocellular foam nanoparticles: Drug loading and release property. Eur. J. Pharm. Biopharm. 2010, 76, 17–23. [Google Scholar] [CrossRef] [PubMed]
  116. Michelina, C.; Ferdinando, P.; Flavia, B.; Simona, P.; Sabina, M.; Paola, N.; Severina, P. Silica/quercetin sol-gel hybrids as antioxidant dental implant materials. Sci. Technol. Adv. Mater. 2015, 16, 035001. [Google Scholar]
  117. Sapino, S.; Ugazio, E.; Gastaldi, L.; Miletto, I.; Berlier, G.; Zonari, D.; Oliaro-Bosso, S. Mesoporous silica as topical nanocarriers for quercetin: Characterization and in vitro studies. Eur. J. Pharm. Biopharm. 2015, 89, 116–125. [Google Scholar] [CrossRef] [PubMed]
  118. Tang, L.; Cheng, J. Nonporous silica nanoparticles for nanomedicine application. Nano Today 2013, 8, 290–312. [Google Scholar] [CrossRef] [PubMed]
  119. Benezra, M.; Penate-Medina, O.; Zanzonico, P.B.; Schaer, D.; Ow, H.; Burns, A.; DeStanchina, E.; Longo, V.; Herz, E.; Iyer, S.; et al. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J. Clin. Investig. 2011, 121, 2768–2780. [Google Scholar] [CrossRef] [PubMed]
  120. Bradbury, M.S.; Phillips, E.; Montero, P.H.; Cheal, S.M.; Stambuk, H.; Durack, J.C.; Sofocleous, C.T.; Meester, R.J.; Wiesner, U.; Patel, S. Clinically-translated silica nanoparticles as dual-modality cancer-targeted probes for image-guided surgery and interventions. Integr. Biol. 2013, 5, 74–86. [Google Scholar] [CrossRef] [PubMed]
  121. Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; le Breton, A.; Preat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control Release 2012, 161, 505–522. [Google Scholar] [CrossRef] [PubMed]
  122. Asghar, W.; Islam, M.; Wadajkar, A.S.; Yuan, W.; Ilyas, A.; Nguyen, K.T.; Iqbal, S.M. PLGA Micro- and Nanoparticles Loaded Into Gelatin Scaffold for Controlled Drug Release. IEEE Trans. Nanotechnol. 2012, 11, 546–553. [Google Scholar] [CrossRef]
  123. Hussein, A.S.; Abdullah, N.; Ahmadun, F.R. In vitro degradation of poly (d,l-lactide-co-glycolide) nanoparticles loaded with linamarin. IET Nanobiotechnol. 2013, 7, 33–41. [Google Scholar] [CrossRef] [PubMed]
  124. Gratton, S.E.; Ropp, P.A.; Pohlhaus, P.D.; Luft, J.C.; Madden, V.J.; Napier, M.E.; DeSimone, J.M. The effect of particle design on cellular internalization pathways. Proc. Natl. Acad. Sci. USA 2008, 105, 11613–11618. [Google Scholar] [CrossRef] [PubMed]
  125. Pimple, S.; Manjappa, A.S.; Ukawala, M.; Murthy, R.S. PLGA nanoparticles loaded with etoposide and quercetin dihydrate individually: In vitro cell line study to ensure advantage of combination therapy. Cancer Nanotechnol. 2012, 3, 25–36. [Google Scholar] [CrossRef] [PubMed]
  126. Pandey, S.K.; Patel, D.K.; Thakur, R.; Mishra, D.P.; Maiti, P.; Haldar, C. Anti-cancer evaluation of quercetin embedded PLA nanoparticles synthesized by emulsified nanoprecipitation. Int. J. Biol. Macromol. 2015, 75, 521–529. [Google Scholar] [CrossRef] [PubMed]
  127. Pool, H.; Quintanar, D.; de Figueroa, J.D.; Mano, C.M.; Bechara, J.E. H.; Godinez, L.A.; Mendoza, S. Antioxidant effects of quercetin and catechin encapsulated into PLGA nanoparticles. J. Nanomater. 2012, 2012. [Google Scholar] [CrossRef]
  128. Bishayee, K.; Khuda-Bukhsh, A.R.; Huh, S.O. PLGA-loaded gold-nanoparticles precipitated with quercetin downregulate HDAC-Akt activities controlling proliferation and activate p53-ROS crosstalk to induce apoptosis in hepatocarcinoma cells. Mol. Cells 2015, 38, 518–527. [Google Scholar] [CrossRef] [PubMed]
  129. Jain, A.K.; Thanki, K.; Jain, S. Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: Implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity. Mol. Pharm. 2013, 10, 3459–3474. [Google Scholar] [CrossRef] [PubMed]
  130. El-Gogary, R.I.; Rubio, N.; Wang, J.T.-W.; Al-Jamal, W.T.; Bourgognon, M.; Kafa, H.; Naeem, M.; Klippstein, R.; Abbate, V.; Leroux, F.; et al. Polyethylene glycol conjugated polymeric nanocapsules for targeted delivery of quercetin to folate-expressing cancer cells in vitro and in vivo. ACS Nano 2014, 8, 1384–1401. [Google Scholar] [CrossRef] [PubMed]
  131. Sharma, G.; Park, J.; Sharma, A.R.; Jung, J.S.; Kim, H.; Chakraborty, C.; Song, D.K.; Lee, S.S.; Nam, J.S. Methoxy poly(ethylene glycol)-poly(lactide) nanoparticles encapsulating quercetin act as an effective anticancer agent by inducing apoptosis in breast cancer. Pharm. Res. 2015, 32, 723–735. [Google Scholar] [CrossRef] [PubMed]
  132. Kumari, A.; Kumar, V.; Yadav, S.K. Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: A green approach. PLoS ONE 2012, 7, e41230. [Google Scholar] [CrossRef] [PubMed]
  133. Ravi Kumar, M.N.V. A review of chitin and chitosan applications. React. Funct. Polym. 2000, 46, 1–27. [Google Scholar] [CrossRef]
  134. Huang, M.; Khor, E.; Lim, L.Y. Uptake and cytotoxicity of chitosan molecules and nanoparticles: Effects of molecular weight and degree of deacetylation. Pharm. Res. 2004, 21, 344–353. [Google Scholar] [CrossRef] [PubMed]
  135. Ma, Z.; Lim, T.M.; Lim, L.Y. Pharmacological activity of peroral chitosan-insulin nanoparticles in diabetic rats. Int. J. Pharm. 2005, 293, 271–280. [Google Scholar] [CrossRef] [PubMed]
  136. Smith, J.M.; Dornish, M.; Wood, E.J. Involvement of protein kinase C in chitosan glutamate-mediated tight junction disruption. Biomaterials 2005, 26, 3269–3276. [Google Scholar] [CrossRef] [PubMed]
  137. Qiao, Y.; Bai, X.F.; Du, Y.G. Chitosan oligosaccharides protect mice from LPS challenge by attenuation of inflammation and oxidative stress. Int. Immunopharmacol. 2011, 11, 121–127. [Google Scholar] [CrossRef] [PubMed]
  138. Liu, H.T.; Li, W.M.; Xu, G.; Li, X.Y.; Bai, X.F.; Wei, P.; Yu, C.; Du, Y.G. Chitosan oligosaccharides attenuate hydrogen peroxide-induced stress injury in human umbilical vein endothelial cells. Pharmacol. Res. 2009, 59, 167–175. [Google Scholar] [CrossRef] [PubMed]
  139. Singla, A.K.; Chawla, M. Chitosan: Some pharmaceutical and biological aspects—An update. J. Pharm. Pharmacol. 2001, 53, 1047–1067. [Google Scholar] [CrossRef] [PubMed]
  140. Sonvico, F.; Cagnani, A.; Rossi, A.; Motta, S.; di Bari, M.T.; Cavatorta, F.; Alonso, M.J.; Deriu, A.; Colombo, P. Formation of self-organized nanoparticles by lecithin/chitosan ionic interaction. Int. J. Pharm. 2006, 324, 67–73. [Google Scholar] [CrossRef] [PubMed]
  141. Raj, L.F.A.A.; Jonisha, R.; Revathi, B.; Jayalakshmy, E. Preparation and characterization of BSA and chitosan nanopartices for sustainable delivery system for quercetin. J. Appl. Pharm. Sci. 2015, 5, 1–5. [Google Scholar] [CrossRef]
  142. Sonaje, K.; Lin, K.J.; Tseng, M.T.; Wey, S.P.; Su, F.Y.; Chuang, E.Y.; Hsu, C.W.; Chen, C.T.; Sung, H.W. Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins. Biomaterials 2011, 32, 8712–8721. [Google Scholar] [CrossRef] [PubMed]
  143. Feng, C.; Wang, Z.; Jiang, C.; Kong, M.; Zhou, X.; Li, Y.; Cheng, X.; Chen, X. Chitosan/O-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: In vitro and in vivo evaluation. Int. J. Pharm. 2013, 457, 158–167. [Google Scholar] [CrossRef] [PubMed]
  144. David, K.I.; Jaidev, L.R.; Sethuraman, S.; Krishnan, U.M. Dual drug loaded chitosan nanoparticles-sugar-coated arsenal against pancreatic cancer. Colloids Surf. B Biointerfaces 2015, 135, 689–698. [Google Scholar] [CrossRef] [PubMed]
  145. Choi, J.S.; Jo, B.W.; Kim, Y.C. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur. J. Pharm. Biopharm. 2004, 57, 313–318. [Google Scholar] [CrossRef] [PubMed]
  146. Wang, X.; Chen, Y.; Dahmani, F.Z.; Yin, L.; Zhou, J.; Yao, J. Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel. Biomaterials 2014, 35, 7654–7665. [Google Scholar] [CrossRef] [PubMed]
  147. Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 2005, 4, 145–160. [Google Scholar] [CrossRef] [PubMed]
  148. Kundu, S.K.; Sharma, A.R.; Lee, S.S.; Sharma, G.; Doss, C.G.; Yagihara, S.; Kim, D.Y.; Nam, J.S.; Chakraborty, C. Recent trends of polymer mediated liposomal gene delivery system. Biomed. Res. Int. 2014, 2014, 934605. [Google Scholar] [CrossRef] [PubMed]
  149. Yuan, F.; Dellian, M.; Fukumura, D.; Leunig, M.; Berk, D.A.; Torchilin, V.P.; Jain, R.K. Vascular permeability in a human tumor xenograft: Molecular size dependence and cutoff size. Cancer Res. 1995, 55, 3752–3756. [Google Scholar] [PubMed]
  150. Stone, W.L.; Smith, M. Therapeutic uses of antioxidant liposomes. Mol. Biotechnol. 2004, 27, 217–230. [Google Scholar] [CrossRef]
  151. Zhang, L.; Gu, F.X.; Chan, J.M.; Wang, A.Z.; Langer, R.S.; Farokhzad, O.C. Nanoparticles in medicine: Therapeutic applications and developments. Clin. Pharmacol. Ther. 2008, 83, 761–769. [Google Scholar] [CrossRef] [PubMed]
  152. Wang, G.; Wang, J.J.; Yang, G.Y.; Du, S.M.; Zeng, N.; Li, D.S.; Li, R.M.; Chen, J.Y.; Feng, J.B.; Yuan, S.H.; et al. Effects of quercetin nanoliposomes on C6 glioma cells through induction of type III programmed cell death. Int. J. Nanomed. 2012, 7, 271–280. [Google Scholar]
  153. Rezaei-Sadabady, R.; Eidi, A.; Zarghami, N.; Barzegar, A. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif. Cells Nanomed. Biotechnol. 2014, 24, 1–7. [Google Scholar] [CrossRef] [PubMed]
  154. Dian, L.; Yu, E.; Chen, X.; Wen, X.; Zhang, Z.; Qin, L.; Wang, Q.; Li, G.; Wu, C. Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles. Nanoscale Res. Lett. 2014, 9. [Google Scholar] [CrossRef] [PubMed]
  155. Tan, B.J.; Liu, Y.; Chang, K.L.; Lim, B.K.; Chiu, G.N. Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. Int. J. Nanomed. 2012, 7, 651–661. [Google Scholar]
  156. Han, Q.; Yang, R.; Li, J.; Liang, W.; Zhang, Y.; Dong, M.; Besenbacher, F.; Wang, C. Enhancement of biological activities of nanostructured hydrophobic drug species. Nanoscale 2012, 4, 2078–2082. [Google Scholar] [CrossRef] [PubMed]
  157. Li, C.; Zhang, J.; Zu, Y.J.; Nie, S.F.; Cao, J.; Wang, Q.; Nie, S.P.; Deng, Z.Y.; Xie, M.Y.; Wang, S. Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals. Chin. J. Nat. Med. 2015, 13, 641–652. [Google Scholar] [CrossRef]
  158. Nair, H.B.; Sung, B.; Yadav, V.R.; Kannappan, R.; Chaturvedi, M.M.; Aggarwal, B.B. Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer. Biochem. Pharmacol. 2010, 80, 1833–1843. [Google Scholar] [CrossRef] [PubMed]
  159. Santos, I.S.; Ponte, B.M.; Boonme, P.; Silva, A.M.; Souto, E.B. Nanoencapsulation of polyphenols for protective effect against colon-rectal cancer. Biotechnol. Adv. 2013, 31, 514–523. [Google Scholar] [CrossRef] [PubMed]
  160. Sanna, V.; Siddiqui, I.A.; Sechi, M.; Mukhtar, H. Nanoformulation of natural products for prevention and therapy of prostate cancer. Cancer Lett. 2013, 334, 142–151. [Google Scholar] [CrossRef] [PubMed]
  161. Parveen, S.; Misra, R.; Sahoo, S.K. Nanoparticles: A boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine 2012, 8, 147–166. [Google Scholar] [CrossRef] [PubMed]
  162. Sun, M.; Nie, S.; Pan, X.; Zhang, R.; Fan, Z.; Wang, S. Quercetin-nanostructured lipid carriers: Characteristics and anti-breast cancer activities in vitro. Colloids Surf. B Biointerfaces 2014, 113, 15–24. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Nam, J.-S.; Sharma, A.R.; Nguyen, L.T.; Chakraborty, C.; Sharma, G.; Lee, S.-S. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine. Molecules 2016, 21, 108. https://doi.org/10.3390/molecules21010108

AMA Style

Nam J-S, Sharma AR, Nguyen LT, Chakraborty C, Sharma G, Lee S-S. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine. Molecules. 2016; 21(1):108. https://doi.org/10.3390/molecules21010108

Chicago/Turabian Style

Nam, Ju-Suk, Ashish Ranjan Sharma, Lich Thi Nguyen, Chiranjib Chakraborty, Garima Sharma, and Sang-Soo Lee. 2016. "Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine" Molecules 21, no. 1: 108. https://doi.org/10.3390/molecules21010108

Article Metrics

Back to TopTop