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Human cancer cells, which contain an enzyme called P450 CYP1B1, were destroyed by a compound contained in tangerine peel
- Thread starter ginfreely
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ABSTRACT
Citrus fruit and in particular flavonoid compounds from citrus peel have been identified as agents with utility in the treatment of cancer. This review provides a background and overview regarding the compounds found within citrus peel with putative anticancer potential as well as the associated in vitro and in vivo studies. Historical studies have identified a number of cellular processes that can be modulated by citrus peel flavonoids including cell proliferation, cell cycle regulation, apoptosis, metastasis, and angiogenesis. More recently, molecular studies have started to elucidate the underlying cell signaling pathways that are responsible for the flavonoids’ mechanism of action. These growing data support further research into the chemopreventative potential of citrus peel extracts, and purified flavonoids in particular. This critical review highlights new research in the field and synthesizes the pathways modulated by flavonoids and other polyphenolic compounds into a generalized schema.
Medicinal Properties of Citrus Fruits
Citrus fruits such as mandarin, pomelo, orange, lime, lemon, and grapefruit have been recognized as having high contents of bioactive compounds (1). Between the pulp and the peel, such fruits contain folate, vitamin C, dietary fiber, and bioactive compounds such as flavonoids. Flavonoids are widely distributed in aromatic plants such as mint and tea but are present in high concentrations in citrus fruits and their peels (2).Citrus peel has untapped potential as a source of medicinal compounds because it contains carotenes, essential oils, pectin, and a range of polyphenolic compounds (3). Epidemiological studies have suggested that high consumption of fruits and vegetables (>400 g/d) can reduce cancer risk by ≥20% (4). The Mediterranean diet is rich in fruit pulp and juice, and the associated high intake of fiber, antioxidants, and polyphenol compounds is linked with a lower cancer risk (5, 6).
The medicinal use of citrus peels can be traced back to the 10th century, but the biological activities of specific chemicals within the peel have only recently been characterized (7, 8). Citrus peels are rich in polyphenolic compounds, which are secondary plant metabolites with diverse and essential biological functions (9, 10).
Polyphenolic compounds consist of various classes of bioactive compounds including flavonoids, limonoids, coumarins, phenolic acids, terpenoids, tannins, stilbenes, lignans, and carotenoids (11–13). They contain heterocycles including aromatic rings with hydroxyl groups in their basic structure (14) and exist in the free state or as glycosides. Flavonoids are likely to be key bioactive compounds in citrus peel, particularly in terms of their anticancer activity (15–17) as well as in the prevention of infectious and degenerative diseases (18–20). Although it is appealing to identify specific molecules with high anticancer activity, there is growing evidence to suggest synergy between bioactive molecules in citrus peel extract (CPE). Whole CPEs have been shown to have higher anticancer activity than the fractionated extracts and isolated single compounds. Indeed, the methanolic extracts and freeze-dried CPEs are correlated with higher concentrations of total phenolic and flavonoid contents (21–23).
Polyphenolic compounds consist of various classes of bioactive compounds including flavonoids, limonoids, coumarins, phenolic acids, terpenoids, tannins, stilbenes, lignans, and carotenoids (11–13). They contain heterocycles including aromatic rings with hydroxyl groups in their basic structure (14) and exist in the free state or as glycosides. Flavonoids are likely to be key bioactive compounds in citrus peel, particularly in terms of their anticancer activity (15–17) as well as in the prevention of infectious and degenerative diseases (18–20). Although it is appealing to identify specific molecules with high anticancer activity, there is growing evidence to suggest synergy between bioactive molecules in citrus peel extract (CPE). Whole CPEs have been shown to have higher anticancer activity than the fractionated extracts and isolated single compounds. Indeed, the methanolic extracts and freeze-dried CPEs are correlated with higher concentrations of total phenolic and flavonoid contents (21–23).
Several salient reviews should be noted. Cirmi et al. (4) detail the range of individual flavonoid and polyphenolic compounds found within citrus fruits and summarize the preclinical and epidemiological evidence for their utility in cancer treatment. Kandaswami et al. (24) describe the general utility of flavonoid compounds (not specifically from citrus) in modulating cell signaling pathways. This critical review focuses on the bioactive compounds that are enriched in citrus peel and examines their underlying mechanism of action. This is timely based on growing efforts to utilize CPEs as chemopreventive agents (25), as well as to leverage their antiatherogenic, anticarcinogenic, anti-inflammatory (26), anticancer (27), antidiarrheal, and antimicrobial properties (3, 28). In this extensive field, such studies are challenging to compare due to a lack of standardized in vitro and in vivo methodologies, as well as the use of whole CPE compared with individual polyphenolics, flavonoids, flavonols, flavones, and polymethoxylated flavones. However, this review explores a range of common mechanisms that feature in preclinical studies including motivation of carcinogen detoxification, scavenging of free radical species, control of cell cycle progression, preventing the initiation of cancer, inhibiting cell proliferation, increasing apoptosis, reducing oncogene activity, prohibiting metastasis and angiogenesis, as well as modulating hormone or growth factor activity (4, 29–32). This involves highlighting both recent and historical reports and synthesizing a model for the different biological functions of CPE bioactives. In most cases there has been no proper follow-up, either in vivo or in clinical research.
Flavonoid Subtypes within CPE
Flavonoids are low molecular weight compounds that are responsible for the vivid color of fruit peels, pulp, and leaves (11). They are found abundantly in citrus fruits, seeds, olive oil, red wine, and tea. More than 9000 flavonoids have been identified to date. Flavonoids feature a basic C6–C3–C6, 15-carbon skeleton. They are comprised of 2 benzene rings (A and B), which are linked via a heterocyclic pyran ring (C in Figure 1). Flavonoids are subdivided according to the presence of an oxy moiety at C4, a double bond between positions 2 and 3, or a hydroxyl group in position 3 of a heterocyclic ring (C in Figure 1).[IMG alt="An external file that holds a picture, illustration, etc.
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FIGURE 1
Main skeleton of flavonoids and their classes.
The biological activities of flavonoids increase with the degree of hydroxylation of the B ring (Figure 1) (24, 33). The basic structure of flavonoids permits a significant number of substitution patterns in the benzene rings A and B within each class of flavonoids: O-sugars, methoxy groups, phenolic hydroxyls, sulfates, and glucuronides (2, 34). The abundance of distinct flavonoids arises from a large number of different combinations of hydroxyl and methoxyl group substitutions. Besides, flavonoids can be classified by variations of the heterocyclic ring C to flavones, flavanones, flavonols, isoflavones, flavans, and anthocyanidins (9, 35).The antioxidant activity of flavonoids is related to ortho‐dihydroxy substitution in ring B, the presence of a 2,3 double bond and of a 4‐oxo moiety in ring C, as well as a 3‐hydroxy‐4‐keto and/or 5‐hydroxy‐4‐keto conformation in rings C and A (36, 37).
Flavonoids with a hydroxyl group in position C3 of the C ring are termed flavonols, and those lacking such an –OH moiety are called flavanones and flavones. Figure 2 illustrates the main structural formulas of some flavonoids isolated from CPE and their structural variations. The main abundant flavonoids in CPE are flavanones such as neohesperidin, naringin, and hesperidin (38–42) as well as nobiletin, sinensetin, and tangeretin (43). The biological activities of flavonoids are related to their antioxidant properties (44). The different degenerative diseases such as brain diseases and Alzheimer disease are affected by flavonoids via their antioxidant properties (42, 45, 46). There is evidence linking the pharmacological activity of CPE flavonoids to their ability to reduce the activity of intracellular signaling molecules including topoisomerases, phosphodiesterases, and kinases, as well as other regulatory enzymes (45, 47).
Flavonoids with a hydroxyl group in position C3 of the C ring are termed flavonols, and those lacking such an –OH moiety are called flavanones and flavones. Figure 2 illustrates the main structural formulas of some flavonoids isolated from CPE and their structural variations. The main abundant flavonoids in CPE are flavanones such as neohesperidin, naringin, and hesperidin (38–42) as well as nobiletin, sinensetin, and tangeretin (43). The biological activities of flavonoids are related to their antioxidant properties (44). The different degenerative diseases such as brain diseases and Alzheimer disease are affected by flavonoids via their antioxidant properties (42, 45, 46). There is evidence linking the pharmacological activity of CPE flavonoids to their ability to reduce the activity of intracellular signaling molecules including topoisomerases, phosphodiesterases, and kinases, as well as other regulatory enzymes (45, 47).
Flavanones (2,3-dihydro-2-phenylchromen-4-one) are a major class of flavonoids and occur mostly in glycoside forms such as hesperidin, neohesperidin, narirutin, naringin, eriocitrin, and neoeriocitrin. The glycosidic forms are divided into 2 types—rutinosides and neohesperidosides. Both rutinose and neohesperidose are glycosylated at position 7 and disaccharides are formed by glucose (Figure 2). The bitter taste of neoeriocitrin, naringin, and neohesperidin is caused by the presence of neohesperidose (rhamnosyl-α-1,2 glucose) in flavanones. Hesperidin, narirutin, and eriocitrin consist of a flavanone bound to rutinose (rhamnosyl-α-1,6 glucose), and they have no taste. The most critical flavanones in aglycone forms are naringenin and hesperetin.
Flavonols (3-hydroxy-2-phenylchromen-4-one), such as kaempferol, quercetin, catechin, and isorhamnetin, are aglycone forms of flavonoids. Flavonols are recognized by the presence of a 2,3-double bond and the 4-oxo group in the C ring. They differ in the presence of 1 additional –OH moiety at position C3 in the C ring. Additionally, the 3-OH group can be glycosylated by different sugars, which significantly increases the number of flavonol isomers (48). The glycoside flavonols such as rutin are found in trace amounts in citrus peel. The predominant types are 3‐O‐monoglycosides, and glycosylation occurs at the 3‐OH group of the C ring (4).
Flavones (2-phenylchromen-4-one) are found in low concentrations in citrus peel. Nevertheless, they can produce important biological activities in vitro and in vivo. For instance, apigenin has shown high anti-inflammatory activity, and diosmin is an important venotonic agent (49, 50). Methylated flavones are the key flavones noted in citrus fruits (51).
Anthocyanidins (2-phenylchromenylium cation) are structurally derived from pyran, flavan, and flavones found only in grapefruit and blood oranges (4). Anthocyanidins are the aglycone counterpart of anthocyanins that are natural pigments of fruits responsible for the fruits’ and flowers’ violet, red, and blue coloring. The color of the anthocyanin occurs in response to changes in pH, oxygen, temperature, light, and enzymes and also by methylation or acylation at the hydroxyl groups on the A and B rings (52).
Polymethoxylated flavones (PMFs) are a subdivision of flavones with ≥2 methoxyl groups on their basic benzo-γ-pyrone skeleton and a carbonyl moiety at the C4 position. Notable PMFs include tangeretin, nobiletin, and sinensetin. PMFs exist exclusively in citrus peels and have been used as herbal (alternative) medicines for decades (49, 53). In research studies, PMFs have shown a broad spectrum of biological activities including anticarcinogenic (54, 55), antioxidant, cardiovascular protection, antiproliferation, antiatherogenic (56, 57), and anti-inflammatory activities (7, 55, 58–60). The permeability of PMFs through biological membranes is higher than other flavonoids because of their planar structure and low polarity (58, 61).
Flavonols (3-hydroxy-2-phenylchromen-4-one), such as kaempferol, quercetin, catechin, and isorhamnetin, are aglycone forms of flavonoids. Flavonols are recognized by the presence of a 2,3-double bond and the 4-oxo group in the C ring. They differ in the presence of 1 additional –OH moiety at position C3 in the C ring. Additionally, the 3-OH group can be glycosylated by different sugars, which significantly increases the number of flavonol isomers (48). The glycoside flavonols such as rutin are found in trace amounts in citrus peel. The predominant types are 3‐O‐monoglycosides, and glycosylation occurs at the 3‐OH group of the C ring (4).
Flavones (2-phenylchromen-4-one) are found in low concentrations in citrus peel. Nevertheless, they can produce important biological activities in vitro and in vivo. For instance, apigenin has shown high anti-inflammatory activity, and diosmin is an important venotonic agent (49, 50). Methylated flavones are the key flavones noted in citrus fruits (51).
Anthocyanidins (2-phenylchromenylium cation) are structurally derived from pyran, flavan, and flavones found only in grapefruit and blood oranges (4). Anthocyanidins are the aglycone counterpart of anthocyanins that are natural pigments of fruits responsible for the fruits’ and flowers’ violet, red, and blue coloring. The color of the anthocyanin occurs in response to changes in pH, oxygen, temperature, light, and enzymes and also by methylation or acylation at the hydroxyl groups on the A and B rings (52).
Polymethoxylated flavones (PMFs) are a subdivision of flavones with ≥2 methoxyl groups on their basic benzo-γ-pyrone skeleton and a carbonyl moiety at the C4 position. Notable PMFs include tangeretin, nobiletin, and sinensetin. PMFs exist exclusively in citrus peels and have been used as herbal (alternative) medicines for decades (49, 53). In research studies, PMFs have shown a broad spectrum of biological activities including anticarcinogenic (54, 55), antioxidant, cardiovascular protection, antiproliferation, antiatherogenic (56, 57), and anti-inflammatory activities (7, 55, 58–60). The permeability of PMFs through biological membranes is higher than other flavonoids because of their planar structure and low polarity (58, 61).
The antioxidant, enzyme-inhibitory, and antiproliferative activities of flavonoids are related to their specific structural features including the presence of glycosylation, the structure oxidation state, and the substituents in both the A and B rings of the flavonoid structure (62, 63). Studies of melanoma cell lines employing several flavonoids of citrus peels have shown the presence of the C2=C3 double bond on the B ring, conjugated with the 4-oxo function, to be critical for this biological activity (64). The presence of ≥3 hydroxyl/methoxyl groups in each ring (A or B) of the flavonoid skeleton significantly increased the antiproliferative activity in human melanoma B16F10 and SK-MEL-1 cell lines (64, 65).
Up to 62 glucoside and aglycone limonoids have been reported in citrus fruits (66). Obacunone glucoside and nomilin acid glucoside are the major limonoid glucosides in CPEs (67). Coumarins are another class of bioactive compounds mainly present in citrus peel. Coumarins such as 7-methoxy-8-(2-oxo-3-methylbutyl) coumarin, 5-geranyloxy-7-methoxycoumarin, auraptene, limettin, and epoxyaurapten, as well as furanocoumarins such as psoralen, xanthotoxin, bergamottin, and epoxybergamottin have been found in citrus peels (68–71). Cinnamic acids (caffeic, p-coumaric, chlorgenic, ferulic, and sinapic) and benzoic acids (protocatechuic, p-hydroxybenzoic, and vanillic) are phenolic acids found in low concentrations in citrus peel (72, 73). Meanwhile, carotenes (β-carotene) and xanthophylls [β-cryptoxanthin, lutein, β-citraurin, violaxanthin, (9Z)-violaxanthin, and zeaxanthin] are the main carotenoids found mostly in citrus peel (72, 74). Apart from the above bioactive compounds, d-limonene is the primary essential oil in citrus peel (75) with anticancer activity in humans (76).
Up to 62 glucoside and aglycone limonoids have been reported in citrus fruits (66). Obacunone glucoside and nomilin acid glucoside are the major limonoid glucosides in CPEs (67). Coumarins are another class of bioactive compounds mainly present in citrus peel. Coumarins such as 7-methoxy-8-(2-oxo-3-methylbutyl) coumarin, 5-geranyloxy-7-methoxycoumarin, auraptene, limettin, and epoxyaurapten, as well as furanocoumarins such as psoralen, xanthotoxin, bergamottin, and epoxybergamottin have been found in citrus peels (68–71). Cinnamic acids (caffeic, p-coumaric, chlorgenic, ferulic, and sinapic) and benzoic acids (protocatechuic, p-hydroxybenzoic, and vanillic) are phenolic acids found in low concentrations in citrus peel (72, 73). Meanwhile, carotenes (β-carotene) and xanthophylls [β-cryptoxanthin, lutein, β-citraurin, violaxanthin, (9Z)-violaxanthin, and zeaxanthin] are the main carotenoids found mostly in citrus peel (72, 74). Apart from the above bioactive compounds, d-limonene is the primary essential oil in citrus peel (75) with anticancer activity in humans (76).
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