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Review

Chemical Structure, Sources and Role of Bioactive Flavonoids in Cancer Prevention: A Review

by
Georgiana Drețcanu
1,†,
Ioana Știrbu
2,†,
Nicolae Leoplold
2,
Daniel Cruceriu
3,4,
Corina Danciu
5,
Andreea Stănilă
1,
Anca Fărcaș
1,
Ileana Monica Borda
6,
Cristian Iuhas
7,* and
Zorița Diaconeasa
1
1
Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea Mănăştur, 400372 Cluj-Napoca, Romania
2
Faculty of Physics, Babes-Bolyai University, Kogalniceanu 1, 400084 Cluj-Napoca, Romania
3
Department of Molecular Biology and Biotechnology, Babes-Bolyai University, 5-7 Clinicilor Street, 400006 Cluj-Napoca, Romania
4
Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania
5
Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania
6
Sixth Department of Medical Specialties, Medical Rehabilitation, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
7
Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400372 Cluj-Napoca, Romania
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Plants 2022, 11(9), 1117; https://doi.org/10.3390/plants11091117
Submission received: 18 March 2022 / Revised: 10 April 2022 / Accepted: 18 April 2022 / Published: 20 April 2022
(This article belongs to the Special Issue Antioxidant Activity of Plant Extracts)
Browse Figures
Versions Notes

Abstract

:
There has been a major shift in the collective mindset around the world in recent decades, both in terms of food and in terms of the treatment of chronic diseases. Increasing numbers of people are choosing to prevent rather than treat, which is why many consumers are choosing plant-based diets, mainly due to their bioactive compounds. A significant case of bioactive compound is flavonoids—a wide subclass of an even wider class of phytochemicals: polyphenols. Flavonoids are a broad topic of study for researchers due to their potential in the prevention and treatment of a broad range of cancers. The aim of this review is to inform/update the reader on the diversity, accessibility and importance of flavonoids as biomolecules that are essential for optimal health, focusing on the potential of these compounds in the prevention of various types of cancer. Along with conventional sources, this review presents some of the possible methods for obtaining significant amounts of flavonoids based on a slightly different approach, genetic manipulation.

Graphical Abstract

1. Introduction

Plants have been a subject of interest for human beings since the beginning of time. First, the symbolistic nature of plants was described in mythology. Some fruits such as lemons were motifs used in the decoration of cultural monuments, while grapes were considered gifts form the gods because of their nutritional value [1]. After that, in ancient times, people extracted phytochemicals from different medicinal plants because they believed that they had healing properties. As time went on, humanity gradually shifted to a meat-based diet thanks to cultural innovation, but in today’s society, the consumption of plant-based foods has become an increasingly approachable lifestyle [2].
Even though in some cultures, such as Christian culture, plants are considered a gift from God for the purpose of nourishing and treating human on Earth [3], fundamentally, plants do not produce these compounds for humans but for their own purposes. Phenolics are in fact secondary metabolites—bioactive substances with both an antioxidant role and an attractive role for pollinators, while also representing a defense mechanism against ultraviolet radiation and several biological pathogens [4].
Polyphenols are a group of phytochemical substances, characterized by the presence of more than one phenol group per molecule [5]. They are classified into different classes such as monophenols, flavonoids, phenolic acids and other non-flavonoid polyphenolics. Even though each subgroup of polyphenols has some well-studied and frequently used representatives, what has gained specific attention from the scientific world are the flavonoids, which are highly diversified pigments that occur ubiquitously in nature. There are several thousands of flavonoids, representing one of the largest groups of naturally occurring products. Flavonoids are widely distributed in plants and are easily recognized as flower pigments, but they occur as well in all parts of the plant.
As the structure of these compounds became increasingly complex and versatile, flavonoids acquired new “responsibilities”, becoming able to manipulate not only the plant cell but also the animal cell. In other words, once the human species began consuming plants, they used these biocompounds for their own purposes to maintain their antioxidant balance and to protect their genetic material, proteins and lipids from possible mutagenic factors, whether internal or external. Of course, during the evolution of science, not only were the beneficial effects of these compounds demonstrated, but also some toxic effects were encountered at the cellular level. If we refer to a normal, healthy cell, cases of toxicity can be observed only in the case of overdoses or the consumption of huge quantities of plant-based foods. On the other hand, if we refer to a modified cell, such as a cancer cell, the phenomenon of inducing toxicity is desirable, because prevention and treatment schemes aim to reduce tumor development. Numerous studies have shown that flavonoids exert pro-oxidative properties on cancer cells, which has intrigued the scientific community worldwide and brought the subject of flavonoids into another perspective: the possible antitumor compound used in prevention/treatment regimens. As phytochemical compounds, their sources of procurement are diverse, so the premises that state that flavonoids can be a good agent for cancer prevention are numerous [6].
In the next chapters, flavonoids will be presented from different perspectives, starting with a short chemical characterization, continuing with some of the richest sources of flavonoids and ending with their implication in cancer prevention.

2. Methods

This paper is an overview of the chemical structure, sources and role of bioactive flavonoids in cancer prevention.
The literature search took place in the PubMed, Web of Science, Scopus and the academic search engine Google Scholar databases. The following keywords were used: flavonoids* AND cancer prevention, flavonoids* AND classification, flavonoids* AND rich dietary sources and flavonoids* AND genetic and metabolic. The results were screened based on their titles, abstracts and full-text availability. All non-English publications were excluded from the present review. Filter limits (such as text availability, article type and publication date) were not applied.

3. Chemical Structure and Classification of Flavonoids

Flavonoids are polyhydroxy-phenolic compounds of the phenylpropanoid biosynthetic pathway in plants [7,8]. They present 15 carbon atoms (C6-C3-C6) that build the structure of two benzene rings joined by a heterocyclic oxygen-centered ring, constituting one of the most characteristic classes of compounds in higher plants. In fact, these compounds are the best-known group of phenolics of mixed biosynthetic origin, where the A ring is synthetized in the polyacetate pathway, the B ring is synthetized in the shikimate pathway and the C ring comes from both of these pathways, as a condensation product of secondary metabolites [9,10]. Many studies have demonstrated common features of flavonoids that are highly important to their different activities, such as their planar structure, the number and position of their substituent groups as well as the presence of the C2-C3 double bond [11].
Flavonoids are classified into various subclasses, based on the substitution patterns of ring C, the oxidation state of the heterocyclic ring and the position of ring B. Therefore, flavonoids are divided into seven major subclasses: flavan-3-ols, flavones, flavonols, flavanones, anthocyanins, chalcones and isoflavonoids (Figure 1). Flavanones, flavones, flavonols, flavan-3-ols and anthocyanins present ring B in position 2 of the heterocyclic ring, and isoflavonoids present ring B in position 3. Flavanones and flavan-3-ols have the central heterocyclic ring saturated and, in this case, one or more chiral centers are present. On the other hand, anthocyanins, isoflavones, flavones and flavonols have the central heterocyclic ring unsaturated, with the molecule being achiral [11]. In the case of chalcones, they represent the only subclass that has a unique structure: it is a little different than usual, but it exerts the same properties. They are precursors in flavonoids and isoflavonoids biosynthesis, having two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl chain. They are found both in the form of cis and trans-isomers, in contrast to the rest of the flavonoid subclasses [12].
As shown in Figure 1, each subclass of flavonoids has different and unique sets of substituents bonded with different carbon atoms, the main ones being -H, -OH, -O/C-Glycoside, -Mannoside, -Galactoside, -Methyl, -Gallate and -Acyl groups. The majority of them can be found in the primary structure of flavonoids in planta (e.g., in fruits, the most stable form of flavonoids is flavonoids-O-glycoside) [11]. The rest can obtain these new substitutes during metabolic processes in the gastrointestinal tract (e.g., in hepatocytes, the main reactions that can occur as part of the phase II metabolism are methylation, glucuronidation and sulphonation) [13].
Although established, these compounds are not the only compounds of this kind produced in the plant kingdom. Recent studies have found so-called neoflavonoids—compounds similar to classical flavonoids but that have certain peculiarities. Neoflavonoids are not produced very often by edible plants but by a variety of plants belonging to families such as Fabaceae, Leguminosae, Rubiaceae, Passifloraceae or Polypodiaceae. Another particularity is that neoflavonoids are also classified into two groups—the dalbergin group (4-phenylcoumarins) and latifolin group (diphenyl allyl compounds)—but the classification depends on the pattern of substitution and on sources. They can present different configurations, as shown in Figure 2, depending on the nature of radicals attached (e.g., -OH, -Glycoside, -Galactoside, -Rhamnoside), and, because of this versatility, they can also be utilized in prevention and treatment schemes, just like flavonoids. It is already known that neoflavonoids exert interesting properties, such as cardiovascular, antidiabetic, antioxidant, antiplasmodial, anti-inflammatory, anti-allergic, anti-melanogenic, antimicrobial, anti-osteoporosis and antileishmanial activity, but also cytotoxic activity against several cancer cell lines [12]. However, because of the fact that neoflavonoids are not considered dietary biocompounds, they are not the subject of this review.

4. Rich Sources of Flavonoids

4.1. Berries and Fruits

Berries seem to capture increasing attention from the general consumer, with both the demand and the supply on the market being in a continuous growth. They possess a wide range of health benefits, the most known being their antioxidant properties, which are strongly related to their high content in flavonoids. Certainly, the phytochemical content varies among cultivars, location, harvesting period and environmental factors, but these variations precisely give the body the biochemical diversity it needs in order to function optimally [14].
Statistically, among all berry-type fruits, blueberries and lingonberries have been shown to contain the highest amounts of flavonoids (1100 mg/100 g dry weight-DW), followed by raspberries and strawberries (500 mg/100 g DW), but many other berries have been reported to be rich in flavonoids as well [15,16]. Besides their high concentration in berries, their chemical properties help them to keep both their stability and biological functions intact, also in products resulting from biotechnological processes. A good example is grapes and their derivatives, such as juices and wines, which also possess a large variety of flavonoids [17]. Studies have shown that wines can reach 2.2 mg/L of total flavonoids [18], and grape juice (verjuice) can reach 2.6 mg rutin equivalent (RE)/mL total flavonoids [19].
From another perspective, a number of researchers have focused on the narrow frame, wanting to find out exactly which compounds give berries, but also fruits, these antioxidant capabilities, thus demonstrating that, for the most part, the most impactful flavonoids in berries are anthocyanins and flavonols (Table 1) [20,21,22,23].
Anthocyanins are naturally occurring pigments responsible for the red, blue and purple colors of fruits. Therefore, the most intense-colored berries are those that possess the highest content of anthocyanins. Various studies have reported the usefulness of anthocyanins. Not only do they serve as nutraceuticals, but they are also considered functional food ingredients, as they are widely used as natural colorants in the food industry [36]. The major compound from the anthocyanin subclass found in berries is cyanidin, but it is found mostly in a glycosylated form, due to its higher stability in the acidic nature of the berries [37].
Anthocyanidins and anthocyanins’ aglycones, such as delphinidin and petunidin, are found in high amounts in blueberries (about 27 and 28 mg/100 g FW), while pelargonidin is dominant in strawberries (about 347 mg/100 g FW) [25].
Other abundant flavonoids found in berries are the compounds from the flavonols subclass. Flavonols are yellow pigments that contain a double bond between C2 and C3 and a -OH group in position 1. As anthocyanins, flavonols are also found in berries in a glycosylated form, usually linked to a glucose or rhamnose molecule [18]. Among all others, quercetin and kaempferol are the most encountered flavonols in almost all berry-type fruits [38,39,40,41,42,43].
Besides berries, citrus fruits are also a great dietary source of bioactive compounds. Flavonols, flavones and flavanones are present in all citrus fruits, known as strong free radical scavengers. Flavanone-O-glycosides, flavone-O/C-glycosides and their derivatives were found to be the most abundant flavonoids in genus Citrus. Naringenin and hesperidin, the main compounds belonging to flavanones subclass, have been reported in citrus fruits, and they are responsible for the bitterness of citrus juices and peel. A study conducted on various fruits and vegetables, including citrus fruits, showed that naringenin and hesperidin were identified in high contents in citrus [29]. Hesperidin was present in higher concentrations in lemon (17 mg/100 g FW), lime (43 mg/100 g FW) and orange (31 mg/100 g FW), while in grapefruits, naringenin had a higher concentration (53 mg/100 g FW) [29].

4.2. Vegetables

Flavonoids represent a significant proportion of the total polyphenol content identified in vegetables, although they are not considered a source of phenolic compounds as rich as fruits. Some of the richest sources of flavonoids include radish (45 ± 1.24 mg catechin equivalents (CE)/100 g FW) and spinach (29 ± 1.24 mg CE/100 g FW), followed by pepper (25 ± 1.63 mg CE/100 g FW), potato (18 ± 0.47 mg CE/100 g FW) and onion (17 ± 2.16 mg CE/100 g FW) [44].
While flavonols are found mostly in bell peppers, chili peppers and lettuce, flavanones are mostly found in tomatoes. Yellow bell pepper is found to contain about 10.2 mg/100 g DW quercetin, 9.5 mg/100 g DW luteolin and a total of 19.8 ± 0.4 mg/100 g DW flavonoids. Green pepper, on the opposite pole, contains only 7.1 ± 0.1 mg/100 g DW quercetin, 6.2 ± 0.5 mg/100 g DW luteolin and a total of 13.7 ± 0.6 mg/100 g DW flavonoids, being the poorest in flavonoids among all the sweet peppers [45,46]. Some other flavonols, such as kaempferol (4.13 ± 0.24 mg/100 g FW) and isorhamnetin (5.3 ± 0.04 mg/100 g FW), were found in high concentrations in vegetables such as onions [30,47].
Flavones such as apigenin and luteolin were identified in vegetables such as kale, radish, celery and cabbage [30], and some considerable amounts of anthocyanins and their aglycones were identified in red onion, purple kale, red radish, red cabbage, purple sweet potato and red cabbage, with cyanidin-glycosides being the main anthocyanins identified (Table 2) [48].

4.3. Spices

Spices and herbs have been widely used in traditional medicine due to their beneficial properties for human health. Several reports have shown that spices and herbs are valuable sources of natural phenolic antioxidants. More than that, spices have been shown to possess much higher antioxidant properties than fruits and vegetables, which were correlated with the total phenolic content. Flavonoids are one of the major phenolics in spices, and they generally occur as glycosylated derivatives [52].
In the U.S. Department of Agriculture (USDA) database (2014), it is suggested that parsley has the highest total flavonoid content (4845.5 mg/100 g), followed by Mexican oregano (1550.79 mg/100 g), celery seeds (841.05 mg/100 g) and Tasmanian pepper (752.68 mg/100 g). Capers also have a high content of flavonoids (493.03 mg/100 g), with saffron (205.48 mg/100 g), dill (112.68 mg/100 g), thyme (47.75 mg/100 g) and rosemary (27.41 mg/100 g) being also in the top list. The spice with the lowest flavonoid content is garlic, with only 3.61 mg/100 g [57].
The main subclass of flavonoids found in spices is flavones (Table 3), with apigenin and luteolin being present usually in aromatic herbs, such as parsley, rosemary, oregano, basil and thyme [52]. Peppermint is a good source of flavanones such as eriodictyol (12.27–54.53 mg/100 g FW) and hesperetin (21.94 mg/100 g FW) [26]. Flavonols such as quercetin and kaempferol were identified in coriander, caraway, oregano, basil, dill and parsley. Other flavonols such as myricetin, rutin and isorhamnetin were identified in different spices. Some of these flavonoids represent the active substance in spices. Therefore, apigenin is the active substance in parsley, luteolin in oregano and celery and kaempferol in capers [58].

4.4. Genetically Modified Organisms

Although most studies acknowledge dietary foods as the main source of phenolic compounds, it is important to recognize that, in order to benefit from the properties of these compounds, relatively high concentrations of the active compound must be consumed, which cannot be obtained only through the consumption of wild-type plants. Thus, some researchers have approached various techniques of bacterial DNA recombination or genetic engineering and editing of plants in order to manipulate the amounts of flavonoids produced.

4.4.1. Plant Genetic Engineering and Editing

Plant genetic engineering is a technique that integrates a desired DNA fragment (recombinant DNA) into another organism’s genome, using basic knowledge of molecular biology. Once this technique is performed, it will result in an improved plant organism, which will perform new functions, produce smaller or larger amounts of compounds or gain some resistance or sensitivity to biotic or abiotic factors, depending on the genes of interest introduced into the body [59].
An interesting approach to producing higher concentrations of flavonoids is the genetic transformation of hop plants via Agrobacterium tumefaciens, which contains an Arabidopsis thaliana regulatory factor construct, such as the production of anthocyanin product 1/A. thaliana’s MYB transcription factor 75 (PAP1/AtMYB75). The transgenic hop plants were reported to have higher concentrations of anthocyanins, rutin, isoquercetin, kaempferol-glucoside, kaempferol-glucoside-malonate, desmethylxanthohumol, xanthohumol, a-acids and b-acids than wild-type plants. Furthermore, the same technique was used successfully for the production of purple tomatoes, cauliflower and rice and red apples with enhanced anthocyanin content [60].
Another study focused on plasmid-mediated transformation via Agrobacterium and was performed by Reddy et al. [61]. They used a rice callus culture that they transformed with Agrobacterium by inserting a plasmid construct into callus cells. The plasmid contained the complementary DNA (cDNA) of the enzyme anthocyanidin synthase (ANS) under a constitutive promotor of mannopine synthase (MAS) (ProMAS: ANS). After the transformation and regeneration, the transgenic plant exhibited an increased antioxidant activity due to the higher levels of anthocyanins and flavonols. These results were obtained because the rice transgenic plant expressed higher levels of ANS, which not only increased the concentrations of anthocyanins and quercetin specifically, but also decreased the proanthocyanidin level in a tissue-specific manner [61].
Similar results were obtained by Schijlen et al. [62], who used a double promotor with constitutive cauliflower mosaic virus double 35S promoter (Pd35S), a gene encoding chalcone isomerase (CHI), a gene encoding flavone synthase (FNS) and Agrobacterium tumefaciens nos terminator (Tnos) for tomato plant transformation. After the transformation, it was observed that tomato peel accumulates higher levels of flavonols such as luteolin aglycone (up to 340 mg/kg FW) and luteolin 7-glucoside (up to 150 mg/kg FW) than the wild-type plant [62].
From other perspective, some researchers managed to enhance flavonoid concentration by mutating (e.g., insertion, deletion, substitution) specific loci in the whole genome. This is called genome editing and is performed especially through specialized constructs of microbiological origin, called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated proteins (Cas) [59]. Zhang et al. [63] tested this novel technology on soya plants (Glycine max) for the purpose of increasing isoflavones content in soya beans. A CRISPR-Cas9 construct was designed to induce triple mutations in order to knock out the genes for flavone synthase (GmFNSII-1) and flavanone-3-hydroxylase (GmF3H1 and GmF3H2). These two enzymes compete with isoflavone synthase (IFS) for naringenin (the substrate). After the editing, mutant soya beans presented a higher level of isoflavones, especially genistein (more than twice the concentration compared to the wild-type), and, because of the higher production of isoflavones, soya leaves presented resistance against soya bean mosaic virus (SMV) [63,64].

4.4.2. Bacterial DNA Recombination

Flavonoids can also be obtained in an alternative way—a path little approached by researchers in the field but that provides excellent results in terms of the quantities obtained. This is also a topic focused on metabolic engineering, but it is not about genetic editing—it is about the recombinant DNA technology which makes the bulk production of different types of flavonoids into a bacterial cell possible, which is an advantage because high concentrations of the compound can be supplied quickly and can be used later for curative purposes. An interesting experiment was performed by Watts and his team [65], who obtained 20.8 mg/L of naringenin in 48 h in recombinant Escherichia coli cultures. They induced cultures of E. coli with genes from Arabidopsis thaliana that would translate the enzymatic package needed for naringenin synthesis [65]. Therefore, the structure of flavonoids is really an advantage, not only in terms of the healing purposes they exhibit but also because of the quick and easy methods of obtaining them in natural and biotechnological ways.
Another similar study made by Lyu et al. [66] revealed the vast possibilities for the production of naringenin in Saccharomyces cerevisiae—a yeast strain. S. cerevisiae was transformed with constructs that summed up the genes responsible for the production of enzymes from the naringenin biosynthetic pathway. They managed to produce about 90 mg/L naringenin from tyrosine (amongst the highest possibilities for de novo microbial production), using shake flask fermentation, which again demonstrates the potential of genetic manipulation in phenolics mass production [66].

5. Flavonoids and Human Health

Phytochemicals have been used for centuries in the production of medicines or foodstuffs whose main purpose was to maintain the health and integrity of the individual [67]. Recently, flavonoids have been the subject of considerable scientific and therapeutic interest, because these natural functional compounds can serve as a starting point for the development of optimal drugs [68].
The advantages of these compounds are numerous, but the most important assets worth considering are their wide distribution, their great structural variety and their low production costs. Furthermore, flavonoids are small organic compounds thats are easily metabolized and absorbed by the human body, and because of that, they could be one of the safest non-immunogenic drugs used in the pharmaceutical industry. In fact, there are many expectations that a wide range of diseases can be successfully treated with newly developed nanoformulations of flavonoids or their derivatives in the near future, since the therapeutic applications of flavonoids normally do not trigger immune reactions [69].
Their use for pharmaceutical purposes is supported by their chemical structure, which makes them responsible for a variety of pharmacological activities. This polyphenolic structure is achieved due to the enzymatic packages held by each plant species, given that flavonoids are, as mentioned above, secondary metabolites in multiple metabolic pathways. It is worth mentioning that, for a mass use of these compounds, enormous concentrations are needed, which can be obtained both naturally and biotechnologically [69].
Flavonoids can be exploited directly from the source through the foods that make up the daily diet or through the extraction of flavonoids and the use of the concentrate in the production of administered nanoformulations. Although the diet method seems to be the easiest one, the problem is that the low bioavailability of flavonoids is an impediment in the absorption of a high concentration of the active compound. Low bioavailability refers to the fact that, once ingested, the compound reaches the systemic circulation with difficulty, resulting in a low rate of cellular absorption due to the high rate of metabolism and poor solubility [70]. That is the reason why increasing numbers of researchers have focused their attention on enhancing the flavonoid concentration and/or on patenting the encapsulation methods by which relatively high amounts of bioactive compound can be transported and protected throughout the body via polymeric coats or diverse matrices and can be transported to target cells [71].
In terms of health properties, many studies have demonstrated their various biological activities including anti-inflammatory, anticancer, antibacterial and antiviral properties. Specific flavonoids were described to function as antioxidants, enzyme inhibitors, epigenetic modulators or even suppressors in some signaling pathways [72,73].
Over the years, researchers have focused mainly on the antioxidant activity of flavonoids, because, as simple as it seems, it targets an important niche in today’s society: pollution. Everyday people are constantly exposed to radiation, air, water and food pollutants, with all being some of the leading causes of oxidative stress. Basically, cells produce persistently reactive species, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), that can cause many cardiovascular and neurodegenerative diseases as well as cancer and metabolic diseases [74]. Antioxidants are specific compounds that protect the cells against the damaging effects of free radicals [75,76].
Flavonoids are the best-known phytochemicals that act as free radicals scavengers and metal chelators [77]. This important property of flavonoids has been the subject of several studies in past years. Although there are plenty of in vitro studies that demonstrate that flavonoids are some of the most important antioxidant molecules in animal cells, the antioxidant efficacy of flavonoids in vivo is less documented due to the poor knowledge about flavonoids’ uptake and bioavailability. However, it is well known that the high daily consumption of flavonoids in the form of vegetables, fruits and beverages may be helpful for scavenging ROS, preventing free-radical damage to biological molecules such as lipids, proteins and DNA [78]. A good example is cranberry extract, which is found to inhibit low-density lipoproteins (LDL) oxidation [79], carcinogenesis [80] and oxidative damage of the vascular endothelium [81], with potential in cancer prevention and therapy.
Since the discovery that free radicals are responsible for a number of pathologies, there has been renewed interest in plant products as a source of natural antioxidants to replace the synthetic ones used in medicine, cosmetics and food. That is the reason why, due to the number of beneficial properties of flavonoids, the aim of this review is also to focus on the latest findings on the potential of flavonoids in cancer prevention.

5.1. Flavonoids in Cancer Prevention

Oncology is a vast and complex research field, summing up multiple signaling pathways that cooperate for the purpose of tumor survival and proliferation. It is well known that conventional anticancer methods cause multiple kinds of damage, both to the tumor and to the whole body, so it is necessary to find alternative methods of treatment. These methods must have many characteristics, among which they must have the ability to modulate the cancer cell from different points of view at the same time. Flavonoids appear to have huge potential in preventing and treating cancer cells, since they are shown to have antitumor activity by various mechanisms, including the induction of apoptosis and cell cycle arrest and the suppression of cell growth and proliferation [82].
The list of preventive properties of flavonoids starts with their ability to affect the initiation and promotion stages of carcinogenesis and continues with the capacity to arrest the cell cycle and to induce apoptosis by downregulating proto-oncogenes, upregulating tumor suppressor genes and inhibiting many cancer-triggering factors [83]. Some of the major effects of flavonoids on tumor cells are illustrated in Figure 3.

5.1.1. Pro-Oxidant and Antioxidant Potential

As mentioned earlier, flavonoids are a subclass of polyphenols mainly known for their antioxidant activity within the cells. This is an important feature, because the implications of a high concentration of ROS can jeopardize cellular integrity, leading to oxidative stress, which represents one of the main causes of cancer [84]. The antioxidant activity of flavonoids is possible due to the hydroxyl groups within their structure—structures that are able not only to reduce ROS but also to inhibit ROS-producing enzymes such as superoxide dismutase, cyclooxygenase, xanthine oxidase or NADPH oxidase; and to induce antioxidant enzymes such as UDP-glucuronyltransferase, glutathione-S-transferase or quinone reductase. Furthermore, flavonoids are able to chelate metal atoms such as iron or copper. All of these mechanisms aim to prevent intracellular lipid peroxidation and protein damage but also DNA and RNA instability (which leads to the formation of loss of function mutations in vital genes such as tumor suppressor genes) [85].
Although this is a crucial property, it does not represent the end of the flavonoids’ properties, because all of these antioxidative mechanisms occur only in the normal cells, thus demonstrating their preventive properties. In tumor cells, however, there is a change in the purpose of these phytochemicals: they are not intended to protect the cancer cell, but, on the contrary, the ultimate goal is to destroy them. The mechanisms are still unclear, but there is a probability that some of the flavonoids, such as luteolin and apigenin, can exert pro-oxidative functions due to glutathione depletion and the inhibition of the superoxide dismutase in several cancer cell lines [85].

5.1.2. DNA Protection and Depletion

It was already noticed that flavonoids have the ability to protect genetic material from inducing potential mutations, but again, this property is only applicable in self-cells. In tumoral cells, flavonoids manage to induce DNA depletion, along with modulating the level of gene expression, which fundamentally represent pro-apoptotic and anti-inflammatory mechanisms. As shown in Figure 2, some of the flavonoids, such as genistein or hesperetin, can upregulate tumor suppression genes, such as BAX or JNK, or can downregulate proto-oncogenes, such as BCL-2, and these genetic modulations lead to apoptosis induction or the inhibition of cell survival and proliferation [86,87].
Moreover, the molecular mechanisms are much more complex; some of them are still unknown, and some of them are applicable for specific compounds, and only in specific cancer cell lines. However, Table 4 attempts to present a bigger picture based on the broad spectrum of action of flavonoids on multiple cancer cell lines.
Besides in vitro studies, there is some information about flavonoids’ capabilities in in vivo models, but this subject is still in its incipient state. Although mostly carcinogenic animal models have been used, especially mice and hamsters, favorable results have appeared regularly. Due to the encapsulation of the compounds, which leads to the avoidance of complications related to the low bioavailability of flavonoids, the clinical results support the hypothesis that flavonoids may be compounds with real therapeutic impact in the future. One study shows that 8.98 µmol/L of quercetin may lead to the suppression of hyperplastic nodules with minimum preneolastic lesions in the parenchyma of rats with hepatic carcinoma induced by diethylnitrosamine treatment [149]. Another study demonstrated that poly (lactic-co-glycolite) nanoparticles loaded with apigenin induce the intrinsic mode of apoptotic cell death and suppress epidermal hyperplasia in Swiss albino mice [150]. Thus, it is safe to say that flavonoids may have a strong impact on tumor cell manipulation in vivo, but this topic needs further study.

6. Conclusions and Future Prospects

Cancer is one of the most controversial and debated subjects regarding human health. Over the years, marked improvements have been made in the search for novel therapies for cancer prevention and/or treatment. Unfortunately, most of the conventional therapies exert harmful side effects or are unaffordable for most patients. Recently, researchers have been focused on finding novel anticarcinogenic agents by investigating naturally occurring bioactive compounds based on the well-known health benefits of various edible plants.
Flavonoids have been shown to possess a variety of health benefits, and many studies suggest that they may be promising candidates in the prevention and treatment of various chronic diseases, including cancer. Their powerful antioxidant activity seems to be key to their therapeutic properties; however, much more work has to be done in order to fully understand their mechanisms of action. Clinical testing should be implemented, especially using nanocarriers loaded with flavonoids such as liposomes, extracellular vesicles, micro-/nanocapsules or emulsions for administration that would target tumor cells in order to draw the bigger picture of the pharmacokinetic processes exerted by flavonoids in the human body. Thus, the paradigm could be changed in terms of the usefulness of these compounds, which could have enormous potential in cancer treatment, not just in prevention. Potential optimal doses for clinical administration could be established with clinical trials.
This study highlights the anticarcinogenic effects of flavonoids on various cancer cell lines based on their biological effects. Moreover, the contents of these phytochemicals in several fruits, vegetables and spices are presented based on reported data in order to give an overview of some of the richest sources of flavonoids. There are also some unconventional sources of flavonoids based on genetically modified organisms—sources that are little-studied by the scientific community so far but with huge potential in the mass production of these phytochemicals. Interdisciplinary genetic and biochemical techniques may be useful in facilitating the production and use of phytochemicals for therapeutic purposes, but the subject still requires ongoing research.
Although this review focuses on dietary plants that contain high concentrations of flavonoids, it is not permissible to neglect an increasingly important topic—the waste left over from the production of food that is our daily diet. It has been shown that waste still contains high concentrations of biologically active compounds, including flavonoids, so studies to support the recirculation of waste for medical purposes would be desirable.
Undoubtedly, the subject of flavonoids has demonstrated a series of advantages (e.g., antioxidant capacity, plant abundance, versatility of compounds) and disadvantages (e.g., low bioavailability, lack of information on the ability of metabolism and absorption of flavonoids by the human body) in time for the scientific world. The biologically active compounds from plant sources have immense medical potential, but future studies need to be conducted in order to demonstrate the already existing properties of these compounds.

Author Contributions

Conceptualization, Z.D., C.I.; writing—original draft preparation, D.C., I.Ș. and C.I.; writing—review and editing, G.D., D.C., N.L., A.F., C.D. and I.M.B.; supervision, C.I.; funding acquisition, A.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by The Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), grant number PN-III-P1-1.1-TE-2019-0960 and grant number PN-III-P4-ID-PCE-2020-2306, within PNCDI III.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

DW Dry weight
RE Rutin equivalent
FW Fresh weight
CE Catechin equivalents
PAP1/AtMYB75 Production of anthocyanin product 1/A. Thaliana’s MYB transcription factor 75
cDNA Complementary DNA
ANS Anthocyanidin synthase
MAS Mannopine synthase
Pd35S Cauliflower mosaic virus double 35S promoter
CHI Chalcone isomerase
FNS Flavone synthase
Tnos Agrobacterium tumefaciens nos terminator
F3H Flavanone-3-hydroxylase
CRISPR Clustered regularly interspaced short palindromic repeats
Cas CRISPR-associated proteins
IFS Isoflavone synthase
SMV Soya bean Mosaic virus
ROS Reactive oxygen species
RNS Reactive nitrogen species
LDL Low-density lipoprotein

References

  1. Atik, M.; Danaci, H.M.; Erdoğan, R. Perception of Plants in Ancient Times and Their Use as Motifs Revealing Aspects of the Cultural Landscape in Side, Turkey. Landsc. Res. 2010, 35, 281–297. [Google Scholar] [CrossRef]
  2. Luca, F.; Perry, G.; Di Rienzo, A. Evolutionary Adaptations to Dietary Changes. Annu. Rev. Nutr. 2010, 30, 291–314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Ogunmefun, O.T. Phytochemicals—God’s Endowment of Curative Power in Plants. Phytochemicals: Source of Antioxidants and Role in Disease Prevention; Asao, T., Asaduzzaman, M., Eds.; IntechOpen: London, UK, 2018; pp. 7–23. [Google Scholar]
  4. Pandey, K.B.; Rizvi, S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell. Longev. 2009, 2, 270–278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Arts, I.C.W.; Hollman, P.C.H. Polyphenols and disease risk in epidemiologic studies. Am. J. Clin. Nutr. 2005, 81 (Suppl. S1), 317S–325S. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Drețcanu, G.; Iuhas, C.I.; Diaconeasa, Z. The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer. Int. J. Mol. Sci. 2021, 22, 8812. [Google Scholar] [CrossRef] [PubMed]
  7. Havsteen, B.H. The biochemistry and medical significance of the flavonoids. Pharmacol. Ther. 2002, 96, 67–202. [Google Scholar] [CrossRef]
  8. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T.C. The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer. Pharmacol. Rev. 2000, 52, 673–751. [Google Scholar]
  9. Pietta, P.-G. Flavonoids as Antioxidants. J. Nat. Prod. 2000, 63, 1035–1042. [Google Scholar] [CrossRef]
  10. Treml, J.; Šmejkal, K. Flavonoids as Potent Scavengers of Hydroxyl Radicals. Compr. Rev. Food Sci. Food Saf. 2016, 15, 720–738. [Google Scholar] [CrossRef]
  11. Kachlicki, P.; Piasecka, A.; Stobiecki, M.; Marczak, Ł. Structural Characterization of Flavonoid Glycoconjugates and Their Derivatives with Mass Spectrometric Techniques. Molecules 2016, 21, 1494. [Google Scholar] [CrossRef] [Green Version]
  12. Gomes, M.N.; Muratov, E.N.; Pereira, M.; Peixoto, J.C.; Rosseto, L.P.; Cravo, P.V.L.; Andrade, C.; Neves, B.J. Chalcone Derivatives: Promising Starting Points for Drug Design. Molecules 2017, 22, 1210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Krga, I.; Monfoulet, L.-E.; Konic-Ristic, A.; Mercier, S.; Glibetic, M.; Morand, C.; Milenkovic, D. Anthocyanins and their gut metabolites reduce the adhesion of monocyte to TNFα-activated endothelial cells at physiologically relevant concentrations. Arch. Biochem. Biophys. 2016, 599, 51–59. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, S.Y.; Lin, H.-S. Antioxidant Activity in Fruits and Leaves of Blackberry, Raspberry, and Strawberry Varies with Cultivar and Developmental Stage. J. Agric. Food Chem. 2000, 48, 140–146. [Google Scholar] [CrossRef] [PubMed]
  15. Liu, J.; Hefni, M.E.; Witthöft, C.M. Characterization of Flavonoid Compounds in Common Swedish Berry Species. Foods 2020, 9, 358. [Google Scholar] [CrossRef] [Green Version]
  16. Veberic, R.; Slatnar, A.; Bizjak, J.; Stampar, F.; Mikulic-Petkovsek, M. Anthocyanin composition of different wild and cultivated berry species. LWT 2015, 60, 509–517. [Google Scholar] [CrossRef]
  17. Castillo-Muñoz, N.; Gómez-Alonso, S.; García-Romero, E.; Hermosín-Gutiérrez, I. Flavonol Profiles of Vitis vinifera Red Grapes and Their Single-Cultivar Wines. J. Agric. Food Chem. 2007, 55, 992–1002. [Google Scholar] [CrossRef]
  18. Gutiérrez-Escobar, R.; Aliaño-González, M.J.; Cantos-Villar, E. Wine Polyphenol Content and Its Influence on Wine Quality and Properties: A Review. Molecules 2021, 26, 718. [Google Scholar] [CrossRef]
  19. Nasser, M.; Cheikh-ali, H.; Hijazi, A.; Merah, O.; Awada, R.; Nasser, M.; Cheikh-ali, H.; Hijazi, A.; Merah, O.; Al-rekaby, A.E.N. Phytochemical Profile, Antioxidant and Antitumor Activities Activities of Green Grape Juice to Cite This Version: Activities of Green Grape Juice. Processes 2020, 1–11. [Google Scholar]
  20. Zhang, J.; Satterfield, M.B.; Brodbelt, J.S.; Britz, S.J.; Clevidence, B.; Novotny, J.A. Structural Characterization and Detection of Kale Flavonoids by Electrospray Ionization Mass Spectrometry Was Found to Reduce the Flavonols to ∼60% of the Levels. Metab. Clin. Exp. 2003, 75, 6401–6407. [Google Scholar]
  21. Määttä-Riihinen, K.R.; Kamal-Eldin, A.A.; Törrönen, A.R. Identification and Quantification of Phenolic Compounds in Berries of Fragaria and Rubus Species (Family Rosaceae). J. Agric. Food Chem. 2004, 52, 6178–6187. [Google Scholar] [CrossRef]
  22. Wu, X.; Beecher, G.R.; Holden, J.M.; Haytowitz, D.B.; Gebhardt, S.E.; Prior, R.L. Concentrations of Anthocyanins in Common Foods in the United States and Estimation of Normal Consumption. J. Agric. Food Chem. 2006, 54, 4069–4075. [Google Scholar] [CrossRef] [PubMed]
  23. Sellappan, S.; Akoh, C.C.; Krewer, G. Phenolic Compounds and Antioxidant Capacity of Georgia-Grown Blueberries and Blackberries. J. Agric. Food Chem. 2002, 50, 2432–2438. [Google Scholar] [CrossRef] [PubMed]
  24. Ljevar, A.; Ćurko, N.; Tomašević, M.; Radošević, K.; Srček, V.G.; Ganić, K.K. Phenolic Composition, Antioxidant Capacity and in vitro Cytotoxicity Assessment of Fruit Wines. Food Technol. Biotechnol. 2016, 54, 145–155. [Google Scholar] [CrossRef] [PubMed]
  25. Marhuenda, J.; Alemán, M.D.; Gironés-Vilaplana, A.; Perez-Garrido, A.; Caravaca, G.; Figueroa, F.; Mulero, J.; Zafrilla, P. Phenolic Composition, Antioxidant Activity, and in vitro Availability of Four Different Berries. J. Chem. 2016, 2016, 5194901. [Google Scholar] [CrossRef] [Green Version]
  26. Guenther, B.; Christensen, C.; Upatnieks, J. Coherent optical processing: Another approach. IEEE J. Quantum Electron. 1979, 15, 1348–1362. [Google Scholar] [CrossRef]
  27. Gu, C.; Howell, K.; Dunshea, F.R.; Suleria, H.A.R. LC-ESI-QTOF/MS Characterisation of Phenolic Acids and Flavonoids in Polyphenol-Rich Fruits and Vegetables and Their Potential Antioxidant Activities. Antioxidants 2019, 8, 405. [Google Scholar] [CrossRef] [Green Version]
  28. Redondo, D.; Arias, E.; Oria, R.; Venturini, M.E. Thinned stone fruits are a source of polyphenols and antioxidant compounds. J. Sci. Food Agric. 2016, 97, 902–910. [Google Scholar] [CrossRef]
  29. Justesen, U.; Knuthsen, P.; Leth, T. Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high-performance liquid chromatography with photo-diode array and mass spectrometric detection. J. Chromatogr. A 1998, 799, 101–110. [Google Scholar] [CrossRef]
  30. Cao, J.; Chen, W.; Zhang, Y.; Zhang, Y.; Zhao, X. Content of Selected Flavonoids in 100 Edible Vegetables and Fruits. Food Sci. Technol. Res. 2010, 16, 395–402. [Google Scholar] [CrossRef] [Green Version]
  31. Gattuso, G.; Barreca, D.; Gargiulli, C.; Leuzzi, U.; Caristi, C. Flavonoid Composition of Citrus Juices. Molecules 2007, 12, 1641–1673. [Google Scholar] [CrossRef] [Green Version]
  32. Hallmann, E.; Rozpara, E.; Słowianek, M.; Leszczynska, J. The effect of organic and conventional farm management on the allergenic potency and bioactive compounds status of apricots (Prunus armeniaca L.). Food Chem. 2018, 279, 171–178. [Google Scholar] [CrossRef] [PubMed]
  33. Qin, F.; Yao, L.; Lu, C.; Li, C.; Zhou, Y.; Su, C.; Chen, B.; Shen, Y. Phenolic composition, antioxidant and antibacterial properties, and in vitro anti-HepG2 cell activities of wild apricot (Armeniaca Sibirica L. Lam) kernel skins. Food Chem. Toxicol. 2019, 129, 354–364. [Google Scholar] [CrossRef] [PubMed]
  34. Cocconi, E.; Stingone, C.; Zanotti, A.; Trifirò, A. Characterization of polyphenols in apricot and peach purees by UHPLC coupled to HRMS Q-Exactive™mass spectrometer: An approach in the identification of adulterations. Biol. Mass Spectrom. 2016, 51, 742–749. [Google Scholar] [CrossRef] [PubMed]
  35. Cheaib, D.; El Darra, N.; Rajha, H.N.; El-Ghazzawi, I.; Mouneimne, Y.; Jammoul, A.; Maroun, R.G.; Louka, N. Study of the Selectivity and Bioactivity of Polyphenols Using Infrared Assisted Extraction from Apricot Pomace Compared to Conventional Methods. Antioxidants 2018, 7, 174. [Google Scholar] [CrossRef] [Green Version]
  36. Koponen, J.M.; Happonen, A.M.; Mattila, P.H.; Törrönen, A.R. Contents of Anthocyanins and Ellagitannins in Selected Foods Consumed in Finland. J. Agric. Food Chem. 2007, 55, 1612–1619. [Google Scholar] [CrossRef]
  37. Khoo, H.E.; Azlan, A.; Tang, S.T.; Lim, S.M. Anthocyanidins and anthocyanins: Colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food Nutr. Res. 2017, 61, 1361779. [Google Scholar] [CrossRef] [Green Version]
  38. Jang, G.H.; Kim, H.W.; Lee, M.K.; Jeong, S.Y.; Bak, A.R.; Lee, D.J.; Kim, J.B. Characterization and quantification of flavonoid glycosides in the Prunus genus by UPLC-DAD-QTOF/MS. Saudi J. Biol. Sci. 2016, 25, 1622–1631. [Google Scholar] [CrossRef]
  39. Tsukamoto, S.; Tomise, K.; Aburatani, M.; Onuki, H.; Hirorta, H.; Ishiharajima, A.E.; Ohta, T. Isolation of Cytochrome P450 Inhibitors from Strawberry Fruit, Fragaria ananassa. J. Nat. Prod. 2004, 67, 1839–1841. [Google Scholar] [CrossRef]
  40. Aaby, K.; Ekeberg, A.D.; Skrede§, G. Characterization of Phenolic Compounds in Strawberry (Fragaria × ananassa) Fruits by Different HPLC Detectors and Contribution of Individual Compounds to Total Antioxidant Capacity. J. Agric. Food Chem. 2007, 55, 4395–4406. [Google Scholar] [CrossRef]
  41. Sandell, M.; Laaksonen, O.; Järvinen, R.; Rostiala, N.; Pohjanheimo, T.; Tiitinen, K.; Kallio, H. Orosensory Profiles and Chemical Composition of Black Currant (Ribes nigrum) Juice and Fractions of Press Residue. J. Agric. Food Chem. 2009, 57, 3718–3728. [Google Scholar] [CrossRef]
  42. Gudej, J. Kaempferol and quercetin glycosides from Rubus idaeus L. leaves. Acta Pol. Pharm. Drug Res. 2004, 60, 313–315. [Google Scholar]
  43. Ek, S.; Kartimo, H.; Mattila, S.; Tolonen, A. Characterization of Phenolic Compounds from Lingonberry (Vaccinium vitis-idaea). J. Agric. Food Chem. 2006, 54, 9834–9842. [Google Scholar] [CrossRef]
  44. Saeed, A.; Marwat, M.S.; Shah, A.H.; Naz, R.; Zain-Ul-Abidin, S.; Akbar, S.; Khan, R.; Navid, M.T.; Saeed, A.; Bhatti, M.Z. Assessment of Total Phenolic and Flavonoid Contents of Selected Fruits and Vegetables. Indian J. Tradit. Knowl. 2019, 18, 686–693. [Google Scholar]
  45. Paul, S.; Geng, C.-A.; Yang, T.-H.; Yang, Y.-P.; Chen, J.-J. Phytochemical and Health-Beneficial Progress of Turnip (Brassica rapa). J. Food Sci. 2018, 84, 19–30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Thuphairo, K.; Sornchan, P.; Suttisansanee, U. Bioactive Compounds, Antioxidant Activity and Inhibition of Key Enzymes Relevant to Alzheimer’s Disease from Sweet Pepper (Capsicum annuum) Extracts. Prev. Nutr. Food Sci. 2019, 24, 327–337. [Google Scholar] [CrossRef] [PubMed]
  47. Fossen, T.; Pedersen, A.T.; Andersen, O.M. Flavonoids from red onion (Allium cepa). Phytochemistry 1998, 47, 281–285. [Google Scholar] [CrossRef]
  48. Tedesco, I.; Carbone, V.; Spagnuolo, C.; Minasi, P.; Russo, G.L. Identification and Quantification of Flavonoids from Two Southern Italian Cultivars of Allium cepa L., Tropea (Red Onion) and Montoro (Copper Onion), and Their Capacity to Protect Human Erythrocytes from Oxidative Stress. J. Agric. Food Chem. 2015, 63, 5229–5238. [Google Scholar] [CrossRef] [PubMed]
  49. Fredotović, Ž.; Šprung, M.; Soldo, B.; Ljubenkov, I.; Budić-Leto, I.; Bilušić, T.; Čikeš-Čulić, V.; Puizina, J. Chemical Composition and Biological Activity of Allium cepa L. and Allium × cornutum (Clementi ex Visiani 1842) Methanolic Extracts. Molecules 2017, 22, 448. [Google Scholar] [CrossRef] [Green Version]
  50. Viña, S.Z.; Chaves, A.R. Respiratory activity and phenolic compounds in pre-cut celery. Food Chem. 2007, 100, 1654–1660. [Google Scholar] [CrossRef]
  51. Yao, Y.; Sang, W.; Zhou, M.; Ren, G. Phenolic Composition and Antioxidant Activities of 11 Celery Cultivars. J. Food Sci. 2010, 75, C9–C13. [Google Scholar] [CrossRef]
  52. Hossain, M.B.; Patras, A.; Barry-Ryan, C.; Martin-Diana, A.B.; Brunton, N. Application of principal component and hierarchical cluster analysis to classify different spices based on in vitro antioxidant activity and individual polyphenolic antioxidant compounds. J. Funct. Foods 2011, 3, 179–189. [Google Scholar] [CrossRef]
  53. Nour, V.; Trandafir, I.; Cosmulescu, S. Bioactive Compounds, Antioxidant Activity and Nutritional Quality of Different Culinary Aromatic Herbs. Not. Bot. Horti Agrobot. Cluj-Napoca 2017, 45, 179–184. [Google Scholar] [CrossRef] [Green Version]
  54. Marincaş, O.; Feher, I.; Magdas, D.A.; Puşcaş, R. Optimized and validated method for simultaneous extraction, identification and quantification of flavonoids and capsaicin, along with isotopic composition, in hot peppers from different regions. Food Chem. 2018, 267, 255–262. [Google Scholar] [CrossRef] [PubMed]
  55. Lee, H.; Oh, I.-N.; Kim, J.; Jung, D.; Cuong, N.P.; Kim, Y.; Lee, J.; Kwon, O.; Park, S.U.; Lim, Y.; et al. Phenolic compound profiles and their seasonal variations in new red-phenotype head-forming Chinese cabbages. LWT 2017, 90, 433–439. [Google Scholar] [CrossRef]
  56. Wiczkowski, W.; Szawara-Nowak, D.; Topolska, J. Changes in the content and composition of anthocyanins in red cabbage and its antioxidant capacity during fermentation, storage and stewing. Food Chem. 2015, 167, 115–123. [Google Scholar] [CrossRef]
  57. Yashin, A.; Yashin, Y.; Xia, X.; Nemzer, B. Antioxidant Activity of Spices and Their Impact on Human Health: A Review. Antioxidants 2017, 6, 70. [Google Scholar] [CrossRef] [Green Version]
  58. Justesen, U.; Knuthsen, P. Composition of flavonoids in fresh herbs and calculation of flavonoid intake by use of herbs in traditional Danish dishes. Food Chem. 2001, 73, 245–250. [Google Scholar] [CrossRef]
  59. Mackelprang, R.; Lemaux, P.G. Genetic Engineering and Editing of Plants: An Analysis of New and Persisting Questions. Annu. Rev. Plant Biol. 2020, 71, 659–687. [Google Scholar] [CrossRef] [Green Version]
  60. Marsafari, M.; Samizadeh, H.; Rabiei, B.; Mehrabi, A.; Koffas, M.; Xu, P. Biotechnological Production of Flavonoids: An Update on Plant Metabolic Engineering, Microbial Host Selection, and Genetically Encoded Biosensors. Biotechnol. J. 2020, 15, e1900432. [Google Scholar] [CrossRef]
  61. Reddy, A.M.; Reddy, V.S.; Scheffler, B.E.; Wienand, U.; Reddy, A.R. Novel transgenic rice overexpressing anthocyanidin synthase accumulates a mixture of flavonoids leading to an increased antioxidant potential. Metab. Eng. 2007, 9, 95–111. [Google Scholar] [CrossRef]
  62. Schijlen, E.; Ric de Vos, C.H.; Jonker, H.; Van Den Broeck, H.; Molthoff, J.; van Tunen, A.; Martens, S.; Bovy, A. Pathway engineering for healthy phytochemicals leading to the production of novel flavonoids in tomato fruit. Plant Biotechnol. J. 2006, 4, 433–444. [Google Scholar] [CrossRef]
  63. Zhang, P.; Du, H.; Wang, J.; Pu, Y.; Yang, C.; Yan, R.; Yang, H.; Cheng, H.; Yu, D. Multiplex CRISPR/Cas9-mediated metabolic engineering increases soya bean isoflavone content and resistance to soya bean mosaic virus. Plant Biotechnol. J. 2019, 18, 1384–1395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Sohn, S.I.; Pandian, S.; Oh, Y.J.; Kang, H.J.; Cho, W.S.; Cho, Y.S. Metabolic Engineering of Isoflavones: An Updated Overview. Front. Plant Sci. 2021, 12, 670103. [Google Scholar] [CrossRef] [PubMed]
  65. Watts, K.T.; Lee, P.C.; Schmidt-Dannert, C. Exploring Recombinant Flavonoid Biosynthesis in Metabolically Engineered Escherichia coli. ChemBioChem 2004, 5, 500–507. [Google Scholar] [CrossRef] [PubMed]
  66. Lyu, X.; Ng, K.R.; Lee, J.L.; Mark, R.; Chen, W.N. Enhancement of Naringenin Biosynthesis from Tyrosine by Metabolic Engineering of Saccharomyces cerevisiae. J. Agric. Food Chem. 2017, 65, 6638–6646. [Google Scholar] [CrossRef] [PubMed]
  67. Sarojini, N.S.; Manjari, A.; Kanti, C. Phytochemical Screening and Anthelmintic Activity Study of Saraca Indica Leaves Extracts. Int. Res. J. Pharm. 2011, 2, 194–197. [Google Scholar]
  68. Zeraik, M.L.; Serteyn, D.; Deby-Dupont, G.; Wauters, J.-N.; Tits, M.; Yariwake, J.H.; Angenot, L.; Franck, T. Evaluation of the antioxidant activity of passion fruit (Passiflora edulis and Passiflora alata) extracts on stimulated neutrophils and myeloperoxidase activity assays. Food Chem. 2011, 128, 259–265. [Google Scholar] [CrossRef]
  69. Mahomoodally, M.F.; Gurib-Fakim, A.; Subratty, A.H. Antimicrobial Activities and Phytochemical Profiles of Endemic Medicinal Plants of Mauritius. Pharm. Biol. 2005, 43, 237–242. [Google Scholar] [CrossRef]
  70. Enaru, B.; Socaci, S.; Farcas, A.; Socaciu, C.; Danciu, C.; Stanila, A.; Diaconeasa, Z. Novel Delivery Systems of Polyphenols and Their Potential Health Benefits. Pharmaceuticals 2021, 14, 946. [Google Scholar] [CrossRef]
  71. Enaru, B.; Dret, G.; Pop, T.D.; St, A. Anthocyanins: Factors Affecting Their Stability and Degradation. Antioxidants 2021, 10, 1967. [Google Scholar] [CrossRef]
  72. Sayed, M.; Mahmoud, A.A.E. Cancer Chemoprevention by Dietary Polyphenols. In Carcinogenesis; IntechOpen: London, UK, 2013. [Google Scholar] [CrossRef] [Green Version]
  73. Pop, T.D.; Diaconeasa, Z. Recent Advances in Phenolic Metabolites and Skin Cancer. Int. J. Mol. Sci. 2021, 22, 9707. [Google Scholar] [CrossRef] [PubMed]
  74. Pucci, C.; Martinelli, C.; Ciofani, G. Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience 2019, 13, 961. [Google Scholar] [CrossRef] [PubMed]
  75. Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002, 13, 572–584. [Google Scholar] [CrossRef]
  76. Kukić, J.; Petrović, S.; Niketić, M. Antioxidant Activity of Four Endemic Stachys Taxa. Biol. Pharm. Bull. 2006, 29, 725–729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Tiwari, A.K. Imbalance in Antioxidant Defence and Human Diseases: Multiple Approach of Natural Antioxidants Therapy. Curr. Sci. 2001, 81, 1179–1187. [Google Scholar]
  78. Yokomizo, A.; Moriwaki, M. Effects of Uptake of Flavonoids on Oxidative Stress Induced by Hydrogen Peroxide in Human Intestinal Caco-2 Cells. Biosci. Biotechnol. Biochem. 2006, 70, 1317–1324. [Google Scholar] [CrossRef] [PubMed]
  79. Porter, M.L.; Krueger, C.G.; Wiebe, D.A.; Cunningham, D.G.; Reed, J.D. Cranberry proanthocyanidins associate with low-density lipoprotein and inhibitin vitro Cu2+-induced oxidation. J. Sci. Food Agric. 2001, 81, 1306–1313. [Google Scholar] [CrossRef]
  80. Neto, C.C.; Amoroso, J.W.; Liberty, A.M. Anticancer activities of cranberry phytochemicals: An update. Mol. Nutr. Food Res. 2008, 52, S18–S27. [Google Scholar] [CrossRef] [PubMed]
  81. Youdim, K.A.; McDonald, J.; Kalt, W.; Joseph, J.A. Potential role of dietary flavonoids in reducing microvascular endothelium vulnerability to oxidative and inflammatory insults. J. Nutr. Biochem. 2002, 13, 282–288. [Google Scholar] [CrossRef]
  82. Gong, G.; Guan, Y.-Y.; Zhang, Z.-L.; Rahman, K.; Wang, S.-J.; Zhou, S.; Luan, X.; Zhang, H. Isorhamnetin: A review of pharmacological effects. Biomed. Pharmacother. 2020, 128, 110301. [Google Scholar] [CrossRef]
  83. Tiwari, P.; Mishra, K.P. Flavonoids sensitize tumor cells to radiation: Molecular mechanisms and relevance to cancer radiotherapy. Int. J. Radiat. Biol. 2019, 96, 360–369. [Google Scholar] [CrossRef] [PubMed]
  84. Zheng, Y.-Z.; Deng, G.; Zhang, Y.-C. Multiple free radical scavenging reactions of flavonoids. Dye. Pigment. 2021, 198, 109877. [Google Scholar] [CrossRef]
  85. Slika, H.; Mansour, H.; Wehbe, N.; Nasser, S.A.; Iratni, R.; Nasrallah, G.; Shaito, A.; Ghaddar, T.; Kobeissy, F.; Eid, A.H. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed. Pharmacother. 2022, 146, 112442. [Google Scholar] [CrossRef]
  86. Lee, S.R.; Kwon, S.W.; Lee, Y.H.; Kaya, P.; Kim, J.M.; Ahn, C.; Jung, E.-M.; Lee, G.-S.; An, B.-S.; Jeung, E.-B.; et al. Dietary intake of genistein suppresses hepatocellular carcinoma through AMPK-mediated apoptosis and anti-inflammation. BMC Cancer 2019, 19, 6. [Google Scholar] [CrossRef] [PubMed]
  87. Palit, S.; Kar, S.; Sharma, G.; Das, P.K. Hesperetin Induces Apoptosis in Breast Carcinoma by Triggering Accumulation of ROS and Activation of ASK1/JNK Pathway. J. Cell. Physiol. 2014, 230, 1729–1739. [Google Scholar] [CrossRef] [PubMed]
  88. Pal, H.C.; Sharma, S.; Elmets, C.A.; Athar, M.; Afaq, F. Fisetin inhibits growth, induces G2/M arrest and apoptosis of human epidermoid carcinoma A431 cells: Role of mitochondrial membrane potential disruption and consequent caspases activation. Exp. Dermatol. 2013, 22, 470–475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Vazhappilly, C.G.; Kumar, D.R.N.; Suresh, P.K.; Kumar, S.; Kumar, R.A. Comparative studies to evaluate relative in vitro potency of luteolin in inducing cell cycle arrest and apoptosis in HaCaT and A375 cells. Asian Pac. J. Cancer Prev. 2013, 14, 631–637. [Google Scholar] [CrossRef] [Green Version]
  90. Zhang, W.; Lan, Y.; Huang, Q.; Hua, Z. Galangin induces B16F10 melanoma cell apoptosis via mitochondrial pathway and sustained activation of p38 MAPK. Cytotechnology 2012, 65, 447–455. [Google Scholar] [CrossRef] [Green Version]
  91. Lee, M.-H.; Huang, Z.; Kim, D.J.; Kim, S.-H.; Kim, M.O.; Lee, S.-Y.; Xie, H.; Park, S.J.; Kim, J.Y.; Kundu, J.K.; et al. Direct Targeting of MEK1/2 and RSK2 by Silybin Induces Cell-Cycle Arrest and Inhibits Melanoma Cell Growth. Cancer Prev. Res. 2013, 6, 455–465. [Google Scholar] [CrossRef] [Green Version]
  92. Pal, H.C.; Sharma, S.; Strickland, L.R.; Katiyar, S.K.; Ballestas, M.E.; Athar, M.; Elmets, C.A.; Afaq, F. Fisetin Inhibits Human Melanoma Cell Invasion through Promotion of Mesenchymal to Epithelial Transition and by Targeting MAPK and NFκB Signaling Pathways. PLoS ONE 2014, 9, e86338. [Google Scholar] [CrossRef] [Green Version]
  93. Diaconeasa, Z.; Ayvaz, H.; Ruginǎ, D.; Leopold, L.F.; Stǎnilǎ, A.; Socaciu, C.; Tăbăran, F.; Luput, L.; Mada, D.C.; Pintea, A.; et al. Melanoma Inhibition by Anthocyanins Is Associated with the Reduction of Oxidative Stress Biomarkers and Changes in Mitochondrial Membrane Potential. Mater. Veg. 2017, 72, 404–410. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, E.; Liu, Y.; Xu, C.; Liu, J. Antiproliferative and proapoptotic activities of anthocyanin and anthocyanidin extracts from blueberry fruits on B16-F10 melanoma cells. Food Nutr. Res. 2017, 61, 1325308. [Google Scholar] [CrossRef] [Green Version]
  95. Su, C.-C.; Wang, C.-J.; Huang, K.-H.; Lee, Y.-J.; Chan, W.-M.; Chang, Y.-C. Anthocyanins from Hibiscus sabdariffa calyx attenuate in vitro and in vivo melanoma cancer metastasis. J. Funct. Foods 2018, 48, 614–631. [Google Scholar] [CrossRef]
  96. Zhang, X.; Liu, X.; Kang, S.; Liu, C.; Hao, Y. Resveratrol enhances the effects of ALA-PDT on skin squamous cells A431 through p38/ MAPK signaling pathway. Cancer Biomark. 2018, 21, 797–803. [Google Scholar] [CrossRef]
  97. Chen, Y.; Chen, H.; Zhang, W.; Ding, Y.; Zhao, T.; Zhang, M.; Mao, G.; Feng, W.; Wu, X.; Yang, L. Bioaccessibility and biotransformation of anthocyanin monomers following in vitro simulated gastric-intestinal digestion and in vivo metabolism in rats. Food Funct. 2019, 10, 6052–6061. [Google Scholar] [CrossRef] [PubMed]
  98. Sun, D.-W.; Zhang, H.-D.; Mao, L.; Mao, C.-F.; Chen, W.; Cui, M.; Ma, R.; Cao, H.-X.; Jing, C.-W.; Wang, Z.; et al. Luteolin Inhibits Breast Cancer Development and Progression In Vitro and In Vivo by Suppressing Notch Signaling and Regulating MiRNAs. Cell. Physiol. Biochem. 2015, 37, 1693–1711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Deb, G.; Thakur, V.S.; Limaye, A.M.; Gupta, S. Epigenetic induction of tissue inhibitor of matrix metalloproteinase-3 by green tea polyphenols in breast cancer cells. Mol. Carcinog. 2014, 54, 485–499. [Google Scholar] [CrossRef]
  100. Seo, H.-S.; Jo, J.K.; Ku, J.M.; Choi, H.-S.; Choi, Y.K.; Woo, J.-K.; Kim, H.I.; Kang, S.-Y.; Lee, K.M.; Nam, K.W.; et al. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells. Biosci. Rep. 2015, 35, e00276. [Google Scholar] [CrossRef] [Green Version]
  101. Azevedo, C.; Correia-Branco, A.; Araújo, J.R.; Guimarães, J.T.; Keating, E.; Martel, F. The Chemopreventive Effect of the Dietary Compound Kaempferol on the MCF-7 Human Breast Cancer Cell Line Is Dependent on Inhibition of Glucose Cellular Uptake. Nutr. Cancer 2015, 67, 504–513. [Google Scholar] [CrossRef]
  102. Liao, W.; Chen, L.; Ma, X.; Jiao, R.; Li, X.; Wang, Y. Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells. Eur. J. Med. Chem. 2016, 114, 24–32. [Google Scholar] [CrossRef]
  103. Li, C.; Yang, D.; Zhao, Y.; Qiu, Y.; Cao, X.; Yu, Y.; Guo, H.; Gu, X.; Yin, X. Inhibitory Effects of Isorhamnetin on the Invasion of Human Breast Carcinoma Cells by Downregulating the Expression and Activity of Matrix Metalloproteinase-2/9. Nutr. Cancer 2015, 67, 1191–1200. [Google Scholar] [CrossRef] [PubMed]
  104. Srinivasan, A.; Thangavel, C.; Liu, Y.; Shoyele, S.; Den, R.B.; Selvakumar, P.; Lakshmikuttyamma, A. Quercetin regulates β-catenin signaling and reduces the migration of triple negative breast cancer. Mol. Carcinog. 2015, 55, 743–756. [Google Scholar] [CrossRef]
  105. Cook, M.T.; Liang, Y.; Besch-Williford, C.; Hyder, S.M. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast Cancer: Targets Ther. 2016, 9, 9–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Lee, J.; Park, S.-H.; Lee, J.; Chun, H.; Choi, M.-K.; Yoon, J.-H.; Pham, T.-H.; Kim, K.H.; Kwon, T.; Ryu, H.-W.; et al. Differential effects of luteolin and its glycosides on invasion and apoptosis in MDA-MB-231 triple-negative breast cancer cells. Excli. J. 2019, 18, 750–763. [Google Scholar] [CrossRef] [PubMed]
  107. Gao, G.; Ge, R.; Li, Y.; Liu, S. Luteolin exhibits anti-breast cancer property through up-regulating miR-203. Artif. Cells Nanomed. Biotechnol. 2019, 47, 3265–3271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Han, F.; Yang, P.; Wang, H.; Fernandes, I.; Mateus, N.; Liu, Y. Digestion and absorption of red grape and wine anthocyanins through the gastrointestinal tract. Trends Food Sci. Technol. 2019, 83, 211–224. [Google Scholar] [CrossRef]
  109. Niazvand, F.; Orazizadeh, M.; Khorsandi, L.; Abbaspour, M.; Mansouri, E.; Khodadadi, A. Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells. Medicina 2019, 55, 114. [Google Scholar] [CrossRef] [Green Version]
  110. Lim, W.; Jeong, W.; Song, G. Delphinidin suppresses proliferation and migration of human ovarian clear cell carcinoma cells through blocking AKT and ERK1/2 MAPK signaling pathways. Mol. Cell. Endocrinol. 2015, 422, 172–181. [Google Scholar] [CrossRef]
  111. Antosiak, A.; Milowska, K.; Maczynska, K.; Rozalska, S.; Gabryelak, T. Cytotoxic activity of genistein-8-C-glucoside form Lupinus luteus L. and genistein against human SK-OV-3 ovarian carcinoma cell line. Med. Chem. Res. 2016, 26, 64–73. [Google Scholar] [CrossRef] [Green Version]
  112. Zhao, Y.; Tian, B.; Wang, Y.; Ding, H. Kaempferol Sensitizes Human Ovarian Cancer Cells-OVCAR-3 and SKOV-3 to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis via JNK/ERK-CHOP Pathway and Up-Regulation of Death Receptors 4 and 5. Med. Sci. Monit. 2017, 23, 5096–5105. [Google Scholar] [CrossRef] [Green Version]
  113. Liu, Y.; Gong, W.; Yang, Z.Y.; Zhou, X.S.; Gong, C.; Zhang, T.R.; Wei, X.; Ma, D.; Ye, F.; Gao, Q.L. Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer. Apoptosis 2017, 22, 544–557. [Google Scholar] [CrossRef] [PubMed]
  114. Gao, Y.; Yin, J.; Rankin, G.O.; Chen, Y.C. Kaempferol Induces G2/M Cell Cycle Arrest via Checkpoint Kinase 2 and Promotes Apoptosis via Death Receptors in Human Ovarian Carcinoma A2780/CP70 Cells. Molecules 2018, 23, 1095. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Teekaraman, D.; Elayapillai, S.P.; Viswanathan, M.P.; Jagadeesan, A. Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line. Chem. Interact. 2019, 300, 91–100. [Google Scholar] [CrossRef] [PubMed]
  116. Tavsan, Z.; Kayali, H.A. Flavonoids showed anticancer effects on the ovarian cancer cells: Involvement of reactive oxygen species, apoptosis, cell cycle and invasion. Biomed. Pharmacother. 2019, 116, 109004. [Google Scholar] [CrossRef] [PubMed]
  117. 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]
  118. Kashafi, E.; Moradzadeh, M.; Mohamadkhani, A.; Erfanian, S. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed. Pharmacother. 2017, 89, 573–577. [Google Scholar] [CrossRef] [PubMed]
  119. Tu, L.-Y.; Bai, H.-H.; Cai, J.-Y.; Deng, S.-P. The mechanism of kaempferol induced apoptosis and inhibited proliferation in human cervical cancer SiHa cell: From macro to nano. Scanning 2016, 38, 644–653. [Google Scholar] [CrossRef] [Green Version]
  120. Tian, T.; Li, J.; Li, B.; Wang, Y.; Li, M.; Ma, D.; Wang, X. Genistein exhibits anti-cancer effects via down-regulating FoxM1 in H446 small-cell lung cancer cells. Tumor Biol. 2013, 35, 4137–4145. [Google Scholar] [CrossRef]
  121. Cho, H.-J.; Ahn, K.-C.; Choi, J.Y.; Hwang, S.-G.; Kim, W.-J.; Um, H.-D.; Park, J.K. Luteolin acts as a radiosensitizer in non-small cell lung cancer cells by enhancing apoptotic cell death through activation of a p38/ROS/caspase cascade. Int. J. Oncol. 2015, 46, 1149–1158. [Google Scholar] [CrossRef] [Green Version]
  122. Jo, E.; Park, S.J.; Choi, Y.S.; Jeon, W.-K.; Kim, B.-C. Kaempferol Suppresses Transforming Growth Factor-β1-Induced Epithelial-to-Mesenchymal Transition and Migration of A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at Threonine-179. Neoplasia 2015, 17, 525–537. [Google Scholar] [CrossRef] [Green Version]
  123. Choi, H.-J.; Chung, T.-W.; Ha, K.-T. Luteolin inhibits recruitment of monocytes and migration of Lewis lung carcinoma cells by suppressing chemokine (C-C motif) ligand 2 expression in tumor-associated macrophage. Biochem. Biophys. Res. Commun. 2016, 470, 101–106. [Google Scholar] [CrossRef] [PubMed]
  124. Yang, Y.; Zang, A.; Jia, Y.; Shang, Y.; Zhang, Z.; Ge, K.; Zhang, J.; Fan, W.; Wang, B. Genistein inhibits A549 human lung cancer cell proliferation via miR-27a and MET signaling. Oncol. Lett. 2016, 12, 2189–2193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Palozza, P.; Simone, R.; Catalano, A.; Boninsegna, A.; Böhm, V.; Fröhlich, K.; Mele, M.C.; Monego, G.; Ranelletti, F.O. Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. J. Nutr. Biochem. 2010, 21, 34–46. [Google Scholar] [CrossRef] [PubMed]
  126. Zhou, Z.; Tang, M.; Liu, Y.; Zhang, Z.; Lu, R.; Lu, J. Apigenin inhibits cell proliferation, migration, and invasion by targeting Akt in the A549 human lung cancer cell line. Anti-Cancer Drugs 2017, 28, 446–456. [Google Scholar] [CrossRef] [PubMed]
  127. Kim, M.-H.; Jeong, Y.-J.; Cho, H.-J.; Hoe, H.-S.; Park, K.-K.; Park, Y.-Y.; Choi, Y.H.; Kim, C.-H.; Chang, H.-W.; Park, Y.-J.; et al. Delphinidin inhibits angiogenesis through the suppression of HIF-1α and VEGF expression in A549 lung cancer cells. Oncol. Rep. 2017, 37, 777–784. [Google Scholar] [CrossRef]
  128. Han, X.; Liu, C.-F.; Gao, N.; Zhao, J.; Xu, J. RETRACTED: Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells. Biomed. Pharmacother. 2018, 108, 809–816. [Google Scholar] [CrossRef]
  129. Wang, J.; Huang, S. Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway. Exp. Ther. Med. 2017, 15, 2667–2673. [Google Scholar] [CrossRef] [Green Version]
  130. Zielińska, M.A.; Białecka, A.; Pietruszka, B.; Hamułka, J. Vegetables and fruit, as a source of bioactive substances, and impact on memory and cognitive function of elderly. Postep. Hig. Med. Dosw. (Online) 2017, 71, 267–280. [Google Scholar] [CrossRef]
  131. Bhardwaj, V.; Mandal, A.K.A. Next-Generation Sequencing Reveals the Role of Epigallocatechin-3-Gallate in Regulating Putative Novel and Known microRNAs Which Target the MAPK Pathway in Non-Small-Cell Lung Cancer A549 Cells. Molecules 2019, 24, 368. [Google Scholar] [CrossRef] [Green Version]
  132. Lee, H.S.; Cho, H.J.; Yu, R.; Lee, K.W.; Chun, H.S.; Park, J.H.Y. Mechanisms Underlying Apoptosis-Inducing Effects of Kaempferol in HT-29 Human Colon Cancer Cells. Int. J. Mol. Sci. 2014, 15, 2722–2737. [Google Scholar] [CrossRef]
  133. Cerezo-Guisado, M.I.; Zur, R.; Lorenzo, M.J.; Risco, A.; Martín-Serrano, M.; Alvarez-Barrientos, A.; Cuenda, A.; Centeno, F. Implication of Akt, ERK1/2 and alternative p38MAPK signalling pathways in human colon cancer cell apoptosis induced by green tea EGCG. Food Chem. Toxicol. 2015, 84, 125–132. [Google Scholar] [CrossRef] [PubMed]
  134. Demoulin, B.; Hermant, M.; Castrogiovanni, C.; Staudt, C.; Dumont, P. Resveratrol induces DNA damage in colon cancer cells by poisoning topoisomerase II and activates the ATM kinase to trigger p53-dependent apoptosis. Toxicol. Vitr. 2015, 29, 1156–1165. [Google Scholar] [CrossRef] [PubMed]
  135. Song, H.M.; Park, G.H.; Eo, H.J.; Jeong, J.B. Naringenin-Mediated ATF3 Expression Contributes to Apoptosis in Human Colon Cancer. Biomol. Ther. 2016, 24, 140–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Qin, J.; Teng, J.; Zhu, Z.; Chen, J.; Huang, W.-J. Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells. Pharm. Biol. 2015, 54, 74–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Yen, H.-R.; Liu, C.-J.; Yeh, C.-C. Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Chem. Interact. 2015, 235, 1–9. [Google Scholar] [CrossRef] [PubMed]
  138. Kunnimalaiyaan, S.; Sokolowski, K.M.; Balamurugan, M.; Gamblin, T.C.; Kunnimalaiyaan, M. Xanthohumol Inhibits Notch Signaling and Induces Apoptosis in Hepatocellular Carcinoma. PLoS ONE 2015, 10, e0127464. [Google Scholar] [CrossRef] [PubMed]
  139. Zhao, X.; Jiang, K.; Liang, B.; Huang, X. Anticancer effect of xanthohumol induces growth inhibition and apoptosis of human liver cancer through NF-κB/p53-apoptosis signaling pathway. Oncol. Rep. 2015, 35, 669–675. [Google Scholar] [CrossRef] [Green Version]
  140. Kavoosi, F.; Sanaei, M.; Valiani, A.; Ghobadifar, M.A. Effect of genistein on apoptosis and proliferation of hepatocellular Carcinoma Hepa1-6 Cell Line. Int. J. Prev. Med. 2018, 9, 12. [Google Scholar] [CrossRef]
  141. Zhu, G.; Liu, X.; Li, H.; Yan, Y.; Hong, X.; Lin, Z. RETRACTED: Kaempferol inhibits proliferation, migration, and invasion of liver cancer HepG2 cells by down-regulation of microRNA-21. Int. J. Immunopathol. Pharmacol. 2018, 32, 1–12. [Google Scholar] [CrossRef] [Green Version]
  142. Sambantham, S.; Radha, M.; Paramasivam, A.; Anandan, B.; Malathi, R.; Chandra, S.R.; Jayaraman, G. Molecular Mechanism Underlying Hesperetin-induced Apoptosis by in silico Analysis and in Prostate Cancer PC-3 Cells. Asian Pac. J. Cancer Prev. 2013, 14, 4347–4352. [Google Scholar] [CrossRef] [Green Version]
  143. Halimah, E.; Diantini, A.; Destiani, D.P.; Pradipta, I.S.; Sastramihardja, H.S.; Lestari, K.; Subarnas, A.; Abdulah, R.; Koyama, H. Induction of caspase cascade pathway by kaempferol-3-O-rhamnoside in LNCaP prostate cancer cell lines. Biomed. Rep. 2014, 3, 115–117. [Google Scholar] [CrossRef] [PubMed]
  144. Selvaraj, S.; Sun, Y.; Sukumaran, P.; Singh, B.B. Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol. Carcinog. 2015, 55, 818–831. [Google Scholar] [CrossRef] [PubMed]
  145. Song, H.; Bao, J.; Wei, Y.; Chen, Y.; Mao, X.; Li, J.; Yang, Z.; Xue, Y. Kaempferol inhibits gastric cancer tumor growth: An in vitro and in vivo study. Oncol. Rep. 2015, 33, 868–874. [Google Scholar] [CrossRef] [PubMed]
  146. Chen, J.; Chen, J.; Li, Z.; Liu, C.; Yin, L. The apoptotic effect of apigenin on human gastric carcinoma cells through mitochondrial signal pathway. Tumor Biol. 2014, 35, 7719–7726. [Google Scholar] [CrossRef]
  147. Zhang, J.; Wu, D.; Vikash; Song, J.; Wang, J.; Yi, J.; Dong, W. Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species. Am. J. Dig. Dis. 2015, 60, 2985–2995. [Google Scholar] [CrossRef]
  148. Feng, J.; Chen, X.; Wang, Y.; Du, Y.; Sun, Q.; Zang, W.; Zhao, G. Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells. Mol. Cell. Biochem. 2015, 408, 163–170. [Google Scholar] [CrossRef]
  149. Khan, H.; Ullah, H.; Martorell, M.; Valdes, S.E.; Belwal, T.; Tejada, S.; Sureda, A.; Kamal, M.A. Flavonoids nanoparticles in cancer: Treatment, prevention and clinical prospects. Semin. Cancer Biol. 2019, 69, 200–211. [Google Scholar] [CrossRef]
  150. Vazhappilly, C.G.; Amararathna, M.; Cyril, A.C.; Linger, R.; Matar, R.; Merheb, M.; Ramadan, W.S.; Radhakrishnan, R.; Rupasinghe, H.V. Current methodologies to refine bioavailability, delivery, and therapeutic efficacy of plant flavonoids in cancer treatment. J. Nutr. Biochem. 2021, 94, 108623. [Google Scholar] [CrossRef]
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Figure 1. Flavonoids classification and their possible chemical structure (created with BioRender.com, accessed on 6 April 2022).
Figure 1. Flavonoids classification and their possible chemical structure (created with BioRender.com, accessed on 6 April 2022).
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Figure 2. Neoflavonoids classification (created with BioRender.com, accessed on 6 April 2022).
Figure 2. Neoflavonoids classification (created with BioRender.com, accessed on 6 April 2022).
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Figure 3. Proposed signaling networks and cell physiological effects mediated by flavonoids.
Figure 3. Proposed signaling networks and cell physiological effects mediated by flavonoids.
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Table
Table 1. Flavonoids found in berries and fruits; FW—fresh weight; DW—dry weight.
Table 1. Flavonoids found in berries and fruits; FW—fresh weight; DW—dry weight.
Source Subclass Major Compounds Conc. mg/100 g FW Conc. mg/100 g DW Conc. mg/100 mL Refs.
Blackberry
(Rubus spp.)		 Flavan-3-ols (+)-Catechin 0.166–1.029 [24]
(−)-Epicatechin 0.012–6.14
Flavonols Quercetin 0.39–1.794 [24]
Anthocyanins Cyanidin-3-glucoside 57.2 ± 2.5 0.039–2.551 [24,25]
Cyanidin-3-rutinoside 25.0 ± 2.8 0.192–11.933
Cyanidin-3-xyloside 48.3 ± 5.6 [25]
Delphinidin-3-glucoside 516.5 ± 9.3
Chokeberry
(Aronia melanocarpa)		 Flavonols Kaempferol 0.00–0.69 [26]
Quercetin 8.90–37.46
Anthocyanins Cyanidin 26.95–947.52 [26]
Delphinidin 0.65
Malvidin 1.22
Pelargonidin 0.51–1.44
Peonidin 0.08
Petunidin 2.79
Blueberry
(Vaccinium angustifolium)		 Anthocyanins Cyanidin-3-glucoside 5.1 ± 0.9 7.7 ± 0.7 [15,25]
Delphinidin-3-glucoside 27.3 ± 3.1 47 ± 2.4
Malvidin-3-glucoside 1.9 ± 0.8 94.3 ± 4.5
Peonidin-3-glucoside 15.1 ± 2.4
Petunidin-3-glucoside 28.1 ± 4.1 37.7 ± 1.9
Flavan-3-ols (+)-Catechin 81.8 ± 9.17 43.1 ± 1.9 [15,27]
(+)-Epicatechin 9.25 ± 0.15
Epicatechin gallate 0.48 ± 0.52
Proanthocyanins 35 ± 1.3 [15]
Flavonols Kaempferol 5.17 ± 0.04 [15,27]
Kaempferol-3-glucoside 5.45 ± 0.24
Quercetin-3-galactoside 0.19 ± 0.09 78.6 ± 1.1
Quercetin-3-glucoside 2.38 ± 0.35
Quercetin-3-glucuronide 1.76 ± 0.12
Cherry
(Prunus spp.)		 Flavan-3-ols (+)-Catechin 0.036–1.117 [24]
(−)-Epicatechin 0.051–2.406
Proanthocyanidins 10.54 ± 0.19 [28]
Flavonols Kaempherol-3-rutinoside 0.03 ± 0.00 [28]
Quercetin 0.026–0.391 [24]
Quercetin-3-rutinoside 0.09 ± 0.01 [28]
Anthocyanins Cyanidin-3-glucoside 0.078–1.207 [24]
Cyanidin-3-
glucosylrutinoside		 0.737–36.128
Cyanidin-3-rutinoside 0.321–9.144
Raspberry
(Rubus idaeus)		 Flavan-3-ols (+)-Catechin 7.4 ± 0.1 0.544–1.540 [15,24]
(−)-Epicatechin 2.94 ± 1.25 102.4 ± 4 2.165–4.359 [15,24,27]
Flavonols Kaempferol-3-glucoside 0.30 ± 0.45 [27]
Quercetin 0.5 0.196–0.392 [24,29]
Quercetin-3-glucoside 0.10 ± 0.32 [27]
Quercetin-3-glucuronide 0.54 ± 0.75
Anthocyanins Cyanidin 3-glucoside 57.5 ± 3.4 74.4 ± 0.8 [15,25]
Cyanidin-3-glucosylrutinoside 56.4 ± 3.8 0.489–2.529 [24,25]
Cyanidin-3-rutinoside 19.6 ± 1.2 0.594–1.072
Cyanidin-3-sophoroside 0.4 ± 0.1 5.783–12.469
Petunidin 3-glucoside 57.5 ± 3.4 [25]
Blackcurrant
(Ribes nigrum)		 Flavonols Quercetin 3.7 ± 0.1 0.2–0.385 [24,29]
Kaempferol 0.1 ± 0.1 [29]
Anthocyanins Cyanidin-3-rutinoside 1.616–8.877 [24]
Delphinidin-3-glucoside 0.22–2.674
Delphinidin-3-rutinoside 2.404–17.921
Strawberry
(Fragaria × ananassa)		 Flavan-3-ols (+)-Catechin 2.51 ± 0.05 45.8 ± 0.5 0.704–0.813 [15,24,27]
(−)-Epicatechin 6.80 ± 2.20 0.153–0.201
Epicatechin gallate 0.45 ± 0.32 [27]
Flavonols Isorhamnetin 0.57 ± 0.01 [30]
Kaempferol 0.28 ± 0.01
0.5 ± 0.3
6.13 ± 0.52		 [27,29,30]
Kaempferol-3-glucoside 1.04 ± 0.28 8 ± 0.1 [15,27]
Quercetin 0.6 ± 0.5
19.0 ± 2.20		 0.031–0.168 [24,27,29]
Quercetin-3-galactoside 0.35 ± 0.49 [27]
Quercetin-3-glucoside 0.20 ± 0.48
Quercetin-3-glucuronide 3.35 ± 1.58
Flavones Apigenin 0.24 ± 0.01 [30]
Anthocyanins Cyanidin 3-rutinoside 0.7 ± 0.1 [25]
Pelargonidin 3-glucoside 347.8 ± 10.5
Pelargonidin 3-rutinoside 52.4 ± 4.8
Peonidin 3-rutinoside 7.6 ± 1.4
Apple
(Malus domestica)		 Flavan-3-ols (+)-Catechin 0.152–1.523 [24]
(−)-Epicatechin 0.414–2.591
Flavonols Isorhamnetin 14.42 ± 0.97 [30]
Kaempferol 5.07 ± 0.71
Quercetin 2.0 ± 0.4
5.16 ± 0.32		 0.04–0.092 [24,29,30]
Flavones Luteolin 1495 ± 45 [30]
Plum
(Prunus spp.)		 Flavonols Isorhamnetin 5.23 ± 0.3 [30]
Kaempferol 3.17 ± 0.12 [30]
Quercetin 1.5
0.34 ± 0.6		 [29,30]
Quercetin 3-rutinoside 15 ± 2 [28]
Flavones Luteolin 3.98 ± 0.04 [30]
Flavan-3-ols Proanthocyanidins 969 ± 187 [28]
Peach
(Prunus persica)		 Flavonols Kaempferol 1.43 ± 0.17 [30]
Kaempherol-3-hexoside 4 ± 1 [28]
Kaempherol-3-rutinoside 5 ± 1
Quercetin 3-rutinoside 6 ± 1
Flavones Luteolin 3.39 ± 0.42 [30]
Flavan-3-ols Proanthocyanidins 1379 ± 62 [28]
Grapes
(Vitis vinifera)		 Flavonols Kaempferol 8.91 ± 0.4
5.35 ± 0.59		 [27,30]
Kaempferol-3-glucoside 0.68 ± 1.2 [27]
Quercetin 1.19 ± 0.03
0.2		 [29,30]
Quercetin-3-glucoside 0.36 ± 0.48 [27]
Quercetin-3-glucuronide 3.11 ± 1.54
Flavan-3-ols Catechin 1.44 ± 0.09 [27]
Epicatechin 2.02 ± 1.17
Epicatechin gallate 0.29 ± 0.30
Orange
(Citrus × sinensis)		 Flavonols Isorhamnetin 0.87 ± 0.08 [30]
Kaempferol 0.51 ± 0.05
Quercetin 0.17 ± 0.02
Flavones Luteolin 0.45 ± 0.04 [30]
6,8-di-C-Glu-Apigenin 4.15–8 [31]
Flavanones Hesperetin 31 ± 2 3.51–55.2 [29,31]
Naringenin 11 ± 2 [29]
Cranberry
(Vaccinium spp.)		 Flavonols Myricetin 23 [29]
Quercetin 16
Grapefruit
(Citrus × paradisi)		 Flavonols Kaempferol 0.4 ± 0.1 [29]
Quercetin 0.5 ± 0.1 0.19 [29,31]
Flavanones Hesperetin 1.5 ± 0.3 0.25–1.79 [29,31]
Naringenin 53 ± 6 0.98–8
Narirutin 2.5–17 [31]
Lemon
(Citrus limon)		 Flavanones Hesperetin 17 3.84–41 [29,31]
Naringenin 0.5 [29]
Flavanones 6,8-di-C-Glu-Apigenin 1–1.45 [31]
6,8-di-C-Glu-Diosmetin 4.05–5.8
7-O-Rut-Luteolin 1.5–6.5
Apricot
(Prunus spp.)		 Flavonols Kaempferol 0.38 ± 0.05
5.44 ± 0.12		 [32,33]
Kaempherol-3-rutinoside 0.03 [28]
Myricetin 0.69 ± 0.07 [32]
Quercetin 4.31 ± 0.07 [33]
Quercetin-3-O-glucoside 7.57 ± 2.87 [32]
Quercetin 3-rutinoside 0.23 ± 0.01 [28]
Rutin 3.77 ± 0.05 0.16–0.26 [33,34]
Flavan-3-ols Catechin 3.14 [35]
Proanthocyanidins 3.04 ± 0.08 [28]
Flavones Apigenin 0.22 ± 0.01 [33]
Apigenin 7-O-glucoside 60.47 ± 1.08
Luteolin 0.68 ± 0.42 [32]
Luteolin 7-xyloside 4.60 ± 0.02 [33]
Anthocyanins Cyanidin 3-(4″-acetylrutinoside) 56.71 ± 1.13 [33]
Cyanidin 3-(6″-acetylglucoside) 11.34 ± 0.16
Cyanidin 3-O-galactoside 4.13 ± 0.05
Cyanidin 3-rutinoside 4.47 ± 0.09
Petunidin 3-galactoside 6.61 ± 0.05
Petunidin 3-rutinoside 2.80 ± 0.05
Table
Table 2. Flavonoids found in vegetables; FW—fresh weight; DW—dry weight.
Table 2. Flavonoids found in vegetables; FW—fresh weight; DW—dry weight.
Source Subclass Major Compounds Conc.
mg/100 g FW		 Conc. mg/100 g DW Refs.
Onion
(Allium cepa)		 Flavonols Isorhamnetin-4′-glucoside 5.398 ± 0.042 [48]
Kaempferol 4.13 ± 0.24 [30]
Quercetin 1.42 ± 0.06
Quercetin-3,4′-diglucoside 29.646 ± 0.005 171.34 ± 0.13 [48,49]
Flavones Apigenin 2.62 ± 0.12 [30]
Anthocyanins Cyanidin-3-(6″-malonylglucoside) 1.718 ± 0.075 [48]
Peonidin-3′-glucoside 0.19 [49]
Kale
(Brassica oleracea var.)		 Flavonols Isorhamnetin 5.98 ± 0.41 [30]
Kaempferol 2.4 ± 0.23
Quercetin 0.48 ± 0.03
Flavones Apigenin 0.28 ± 0.02 [30]
Luteolin 2.39 ± 0.2
Celery
(Apium graveolens)		 Flavones Apigenin 13.93 ± 0.52
0.461		 79.42 ± 0.77 [30,50,51]
Apigenin-7-O-glucoside 156 ± 7 [52]
Luteolin 2.31 ± 0.11
0.088		 62.43 ± 0.59 [30,50,51]
Luteolin-7-O-glucoside 654 ± 8 [52]
Flavonols Kaempferol 0.46 ± 0.03 1.06 ± 0.03 [30,51]
Myricetin 105.05 ± 4.46 [53]
Rutin 13.99 ± 0.58
Quercetin 5.31 ± 0.21
Flavan-3-ols Epicatechin 8.90 ± 0.42 [53]
Chili pepper
(Capsicum var.)		 Flavonols Isoquercetin 1.742 ± 0.055 [54]
Kaempferol-3-glucoside 3.479 ± 0.02
Myricetin 2.388 ± 0.06
Quercetin 0.16 ± 0.02 [30]
Flavones Apigenin 0.5 [30]
Luteolin 2.54 ± 0.05
Radish
(Raphanus raphanistrum subsp. sativus)		 Flavonols Kaempferol 3.23 ± 0.44 [30]
Quercetin 0.52 ± 0.07
Flavones Apigenin 0.22 ± 0.03 [30]
Luteolin 1.95 ± 0.27
Soybean
(Glycine max)		 Flavonols Quercetin 0.17 [30]
Flavones Luteolin 0.94 ± 0.12 [30]
Spinach
(Spinacia oleracea)		 Flavonols Kaempferol 0.89 ± 0.04 [30]
Cabbage
(Brassica oleracea)		 Flavonols Kaempferol 3.12 ± 0.02 11.0 ± 0.8 [30,55]
Quercetin 0.49 16.1 ± 1.0
Flavones Luteolin 3.27 ± 0.02 [30]
Anthocyanins Cyanidin-3,5-O-diglucoside 3.2 [56]
Cyanidin-3-(feruloyl)-diglucoside-5-glucoside 7.3
Cyanidin-3-(sinapoyl)-O-diglucoside-5-O-glucoside 2.7
Cyanidin-3-coumaroyl-dihexoside-5-hexoside 9.4
Broccoli
(Brassica oleracea var. italica)		 Flavonols Kaempferol 211 ± 6 [30]
Quercetin 0.53 ± 0.03
Table
Table 3. Flavonoids found in spices; FW—fresh weight; DW—dry weight.
Table 3. Flavonoids found in spices; FW—fresh weight; DW—dry weight.
Source Subclass Major Compounds Conc. mg/100 g FW Conc. mg/100 g DW Ref.
Celery
(Apium graveolens)		 Flavones Apigenin-7-O-glucoside 156 ± 7 [52]
Luteolin-7-O-glucoside 654 ± 8
Cumin
(Cuminum cyminum)		 Flavones Apigenin-7-O-glucoside 146 ± 2 [52]
Luteolin-7-O-glucoside 224 ± 7
Dill
(Anethum graveolens)		 Flavonols Isorhamnetin 15–72 [58]
Kaempferol 16–24
Quercetin 48–110
Oregano (Origanum vulgare) Flavones Apigenin 2–4 [58]
Apigenin-7-O-glucoside 254 ± 1 [52]
Luteolin 0–3 [58]
Luteolin-7-O-glucoside 301 ± 1 [52]
Fennel
(Foeniculum vulgare)		 Flavones Apigenin-7-O-glucoside 43 ± 1 [52]
Luteolin-7-O-glucoside 211 ± 4
Cress
(Lepidium sativum)		 Flavonols Isorhamnetin 1 [58]
Kaempferol 13
Basil
(Ocimum basilicum)		 Flavones Apigenin-7-O-glucoside 18 [52]
Luteolin-7-O-glucoside 127 ± 1
Marjoram
(Origanum majorana)		 Flavones Apigenin-7-O-glucoside 83 ± 3 [52]
Luteolin-7-O-glucoside 461 ± 7
Chives
(Allium schoenoprasum)		 Flavonols Isorhamnetin 5 [58]
Kaempferol 12
Quercetin 3
Parsley
(Petroselinum
crispum)		 Flavones Apigenin 0.44 ± 0.01 [30]
Apigenin-7-O-glucoside 752 ± 17 [52]
Luteolin 1.42 ± 0.03 [30]
Luteolin-7-O-glucoside 125 ± 8 [52]
Flavonols Isorhamnetin 1.12 ± 0.1 [30]
Kaempferol 1.85 ± 0.03
Myricetin 151.03 ± 6.68 [53]
Quercetin 0–1
0.5 ± 0.01
71.33 ± 2.19		 [30,53,58]
Rutin 4.32 ± 0.23 [53]
Flavan-3-ols Epicatechin 2.67 ± 0.11 [53]
Thyme
(Thymus vulgaris)		 Flavones Apigenin 5 [58]
Apigenin-7-O-glucoside 16 [52]
Luteolin 51 [58]
Luteolin-7-O-glucoside 104 ± 2 [52]
Lovage
(Levisticum officinale)		 Flavonols Kaempferol 7 [58]
Quercetin 170
Coriander
(Coriandrum sativum)		 Flavonols Quercetin 5 [58]
Rosemary (Rosmarinus officinalis) Flavones Apigenin-7-O-glucoside 50 ± 1 [52]
Luteolin 4 [58]
Luteolin-7-O-glucoside 71 ± 2 [52]
Mint
(Mentha var.)		 Flavones Apigenin 18–99 [58]
Luteolin 11–41
Sage
(Salvia officinalis)		 Flavones Apigenin-7-O-glucoside 53 ± 1 [52]
Luteolin-7-O-glucoside 495 ± 1
Watercress
(Nasturtium officinale)		 Flavonols Kaempferol 1 [58]
Quercetin 4 [58]
Cinnamon
(Cinnamomum var.)		 Flavan-3-ols Proanthocyanins 8960 [28]
Tarragon (Artemisia dranunculus) Flavonols Isorhamnetin 5 [58]
Kaempferol 11
Quercetin 10
Flavones Luteolin 1
Table
Table 4. Biological activities of flavonoids; ↑—induction, activation, upregulation, elevation; ↓—suppression, inactivation, downregulation, block.
Table 4. Biological activities of flavonoids; ↑—induction, activation, upregulation, elevation; ↓—suppression, inactivation, downregulation, block.
Cancer Type Cell Line Compound Conc. Main Biological Effects Ref.
Skin cancer A431, SCC-13 Fisetin 0–80 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↓ Cell viability
↓ Colony formation
↓ Δψm		 [88]
A375 Luteolin 0–80 µM ↑ Apoptosis
↑ Cell cycle arrest at G0/G1 phase
↓ Colony formation
↓ Cell proliferation		 [89]
B16F10 Galangin 0–100 µmol/L ↑ Phosphor-p-38 MAPK
↑ Apoptosis
↓ Δψm
↓ Cell viability		 [90]
SK-MEL-5, SK-MEL-28 Silybin 0–80 µM ↑ Cell cycle arrest at G1 phase
↓ Cell viability
↓ Cell proliferation
↓ Kinase activity of MEK1/2 and RSK2
↓ Expression of NF-κB, Ap-1 and STAT3
↓ Phosphorylation of ERK1/2 and RSK2		 [91]
A375, RPMI-7951, Hs294T Fisetin 0–20 µM ↓ Cell invasion
↓ Phosphorylation of MEK1/2 and ERK1/2
↓ Activation of IKK
↓ Activation of the NF-κB signaling pathway		 [92]
B16-F10 Anthocyanins 0–500 µg/mL ↓ Cell proliferation [93]
0–800 μg/mL ↑ Cell cycle arrest at G0/G1 phase
↑ Apoptosis
↓ Cell viability
↓ Cell proliferation		 [94]
B16-F1 Anthocyanins 0–1 mg/mL ↓ Cell growth
↓ Cell migration
↓ Tube formation
↓ Expression of MMP-2/-9 and VEGF
↓ Angiogenesis		 [95]
A431 Resveratrol + ALA-PDT therapy 0–120 mg/mL ↑ Apoptosis
↑ MAPK pathway
↓ Cell proliferation		 [96]
A375.S2 Chrysin 0–15 µM ↑ Cell morphological changes
↓ Cell viability
↓ Cell migration and invasion
↓ Expression of MMP-2
↓ Expression of NF-κB p65		 [97]
Breast cancer MDA-MB-231, MCF-7 Luteolin 0–100 µM ↓ Cell viability
↓ Cell migration
↓ Expression of Notch-1, Hes-1, Hey, VEGF, Cyclin D1 and MMP
-Regulating miRNAs		 [98]
MCF-7, MDA-MB-231 Epigallocatechin-3-gallate 0–40 µM ↑ TIMP
-3 levels↓ Cell proliferation by restoring the MP/TIMP balance		 [99]
MCF-7 Hesperetin 0–200 µM ↑ ROS generation
↑ ASK1/JNK pathway
↑ Apoptosis
↓ Δψm		 [87]
BT-474 Apigenin 0–100 µM ↑ Apoptosis
↓ STAT3 signaling
↓ Cell proliferation
↓ Chlorogenic survival		 [100]
MCF-7 Kaempferol 0–100 µM ↑ Extracellular lactate levels
↓ Cell proliferation
↓ Glucose uptake		 [101]
0–100 mg/mL ↑ Apoptosis
↓ Cell proliferation
↓ Δψm		 [102]
MDA-MB-231 Isorhamnetin 0–40 µM ↓ Cell proliferation
↓ Cell migration
↓ Cell adhesion
↓ Expression of MMP-2 and MMP-9		 [103]
MDA-MB-231, MDA-MB-468 Quercetin 0–100 µM ↓ Cell proliferation
↓ Cell viability
↓ β-Catenin		 [104]
MDA-MB-231 (4175) LM2, MDA-MB-435 Luteolin 0–100 µM ↑ Apoptosis
↓ Cell migration
↓ Cell viability
↓ VEGF secretion		 [105]
MDA-MB-231 Luteolin 0–40 µM ↑ Apoptosis
↓ Cell viability
↓ Expression of MMP-9
↓ Cell migration
↓ Cell invasion		 [106]
MDA-MB-453, MCF-7 Luteolin 10 µM ↑ Apoptosis
↑ Expression of miR-203
↓ Cell viability
↓ Ras/Raf/MEK/ERK signaling pathways		 [107]
MDA-MB-231, MCF-7, MDA-MB-453 Delphinidin 40 μmol/L ↓ Cell viability
↓ Cell proliferation
↓ Cell migration
↓ Wnt/β-catenin signaling pathway
-Modulating miR-34a and HOTAIR		 [108]
MCF-7 Quercetin 25 μmol/mL ↑ Apoptosis
↑ ROS levels and MDA
↓ Cell viability
↓ Cell proliferation
↓ Antioxidant enzymes activity		 [109]
Ovarian cancer ES2 Delphinidin 0–100 µM ↑ Apoptosis
↓ Cell proliferation
↓ Cell migration
↓ AKT, ERK1/2, and MAPK signaling pathways		 [110]
SK-OV-3 Genistein 0–90 µM ↑ Apoptosis
↓ Cell proliferation
↓ Δψm		 [111]
OVCAR-3, SKOV-3 Kaempferol 0–100 µM ↑ Apoptosis
↑ Expression of DR4, DR5, CHOP, JNK, ERK1/2, p38
↓ Cell proliferation
-Modulates the expression of apoptotic pathway proteins		 [112]
CAOV3 Quercetin 0–100 µM ↑ Apoptosis
↓ Cell viability		 [113]
A2780/CP70, OVCAR-3 Kaempferol 0–50 µM ↑ Cell cycle arrest at G2/M phase via Chk2
↑ Apoptosis via death receptors
↓ Cell viability		 [114]
PA-1 Quercetin 0–200 µM ↑ Apoptosis
↓ Cell viability
↓ Bcl-2, Bcl-xL		 [115]
A2780, OVCAR-3, SKOV-3 Apigenin
Luteolin
Myricetin		 0–100 µM ↑ ROS levels
↑ MDA levels
↑ Apoptosis
↑ Cell cycle arrest at G0/G1 and G2/M phase
↓ Cell viability		 [116]
Cervical cancer HeLa Quercetin 0–100 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↑ ROS levels
↓ Cell proliferation
↓ Δψm		 [117]
HeLa Kaempferol 0–100 mg/mL ↓ Cell proliferation [102]
2.5–100 µM ↑ Bax
↓ Expression of Cyclin B1
↓ Expression of CDK1
↓ NF-κB nuclear translocation
↓ Bcl-2		 [6]
0–100 µM ↑ Apoptosis
↓ Cell viability
↓ PI3K/AKT and hTERT pathways		 [118]
SiHa Kaempferol 0–100 µg/mL ↑ Apoptosis
↑ Intracellular free Ca2+
↓ Cell proliferation
↓ Δψm		 [119]
Lung cancer H446 Genistein 0–100 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↓ Cell proliferation
↓ Cell migration		 [120]
NCI-H1299, -H460 Luteolin 0–50 µM ↑ Apoptosis
↓ Cell viability		 [121]
A549 Kaempferol 0–50 µM ↓ Cell proliferation
↓ Cell migration
↓ TGF-β1-induced EMT		 [122]
0–100 mg/mL ↓ Cell proliferation [102]
RAW 264.7 Luteolin 0–30 µM ↓ Cell proliferation
↓ Cell migration
↓ STAT6 phosphorylation and the TAM phenotype
↓ Expression of CCL2 and migration of monocytes		 [123]
A549 Genistein 0–200 µM ↑ Apoptosis
↑ Bax mRNA level
↑ Expression of miR-27a
↓ Cell proliferation
↓ Cell viability
↓ Bcl-2 mRNA level
↓ Expression of MET protein		 [124,125]
A549 Apigenin 0–100 µM ↓ Cell proliferation
↓ Cell migration and invasion by targeting the PI3K/Akt signaling pathway		 [126]
A549, H1299 Daidzein 0–80 µmol/L ↑ Apoptosis
↓ Cell proliferation		 [41]
A549 Delphinidin 0–80 µM ↓ Cell proliferation
↓ ERK, mTOR and p70S6K signaling pathways		 [127]
A549 Kaempferol 0–50 µM ↑ Apoptosis
↑ Expression of miR-340
↓ Cell proliferation
↓ Cell viability
↓ Expression of Cyclin D1
↓ p-PI3K and p-AKT levels		 [128]
A549 Fisetin 0–40 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↓ Cell viability
↓ Cell proliferation
↓ Cell adhesion
↓ Cell invasion
↓ Cell migration
↓ ERK signaling pathway via MEK1/2		 [129]
H1299, A549 Epigallocatechin-3-gallate 0–40 µM ↑ Apoptosis
↓ Cell proliferation
↓ Expression of p-PI3K and p-Akt		 [130]
A549 Hesperetin 0–100 µM ↓ Cell proliferation [9]
A549 Epigallocatechin-3
-gallate		 40 µM ↑ miR-155
↑ Cell cycle arrest at G0/G1 phase
↓ Cell proliferation
↓ miR-212		 [131]
Colon cancer HT-29 Kaempferol 0–60 µmol/L ↑ Apoptosis
↓ Δψm		 [132]
HT-29 Epigallocatechin-3-gallate 0–50 µM ↑ MAPK and Akt signaling pathways
↓ p38 and ERK1/2 signaling pathways		 [133]
HCT-116 Resveratrol 0–150 µM ↑ Apoptosis
↑ DNA damage		 [134]
HCT-116, SW480, LoVo, HT-29 Naringenin 0–200 µM ↑ Apoptosis
↓ Cell viability		 [135]
HCT-116, LoVo Genistein 0–100 µM ↑ Apoptosis
↑ Bax mRNA level
↓ Cell proliferation
↓ Cell viability
↓ Phosphorylation of Akt		 [136]
Liver cancer HepG2, Huh-7, HA22T Naringenin 0–100 µM ↓ Cell proliferation
↓ TPA-induced cancer cell proliferation		 [137]
Huh-7, HepG2, Hep3B, SK-Hep-1 Xanthohumol 0–15 µM ↑ Apoptosis
↓ Cell viability
↓ Colony forming
↓ Notch1 signaling		 [138]
HepG2 Xanthohumol 0–40 µM ↓ cell proliferation
↑ Apoptosis
-modulates NK-kB/p53 signaling pathways		 [139]
Hepa1-6 Genistein 0–100 µM ↑ Apoptosis
↓ Cell viability
↓ Cell proliferation		 [140]
HepG2 Kaempferol 0–100 µM ↑ Apoptosis
↓ Cell proliferation
↓ Cell migration
↓ Cell invasion
↓ Expression of miR-2I		 [141]
Prostate cancer PC-3 Hesperetin 0–120 µM ↑ Apoptosis
↓ Cell proliferation
↓ NK-kB signaling pathway		 [142]
LNCaP Kaempferol-3-O-rhamnoside 0–926 µM ↑ Apoptosis
↓ Cell proliferation		 [143]
PC-3, DU145 Resveratrol 0–100 µM ↑ Autophagy cell death [144]
Gastric cancer SGC-7901, MKN28 Kaempferol 0–200 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↓ Cell proliferation
↓ Cell viability		 [145]
HGC-27, SGC-7901 Apigenin 0–20 µg/mL ↑ Apoptosis
↓ Cell proliferation
↓ Δψm		 [146]
SGC-7901, MGC-803, HGC-27 Hesperetin 0–400 µM ↑ Apoptosis
↓ Cell proliferation
↓ Δψm
↓ Cell viability
↓ ROS levels		 [147]
HGC-27, SGC-7901 Myricetin 0–40 µM ↑ Apoptosis
↑ Cell cycle arrest at G2/M phase
↓ Cell proliferation		 [148]
SCG-7901 Kaempferol 0–100 mg/mL ↓ Cell proliferation [102]
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Drețcanu, G.; Știrbu, I.; Leoplold, N.; Cruceriu, D.; Danciu, C.; Stănilă, A.; Fărcaș, A.; Borda, I.M.; Iuhas, C.; Diaconeasa, Z. Chemical Structure, Sources and Role of Bioactive Flavonoids in Cancer Prevention: A Review. Plants 2022, 11, 1117. https://doi.org/10.3390/plants11091117

AMA Style

Drețcanu G, Știrbu I, Leoplold N, Cruceriu D, Danciu C, Stănilă A, Fărcaș A, Borda IM, Iuhas C, Diaconeasa Z. Chemical Structure, Sources and Role of Bioactive Flavonoids in Cancer Prevention: A Review. Plants. 2022; 11(9):1117. https://doi.org/10.3390/plants11091117

Chicago/Turabian Style

Drețcanu, Georgiana, Ioana Știrbu, Nicolae Leoplold, Daniel Cruceriu, Corina Danciu, Andreea Stănilă, Anca Fărcaș, Ileana Monica Borda, Cristian Iuhas, and Zorița Diaconeasa. 2022. "Chemical Structure, Sources and Role of Bioactive Flavonoids in Cancer Prevention: A Review" Plants 11, no. 9: 1117. https://doi.org/10.3390/plants11091117

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