Cancer: Prostate
Action: Chemo-preventive, anti-oxidant, modulate insulin-like growth factor-I (IGF-I)
Natural phenolic compounds play an important role in cancer prevention and treatment. Phenolic compounds from medicinal herbs and dietary plants include phenolic acids, flavonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and others. Various bioactivities of phenolic compounds are responsible for their chemo-preventive properties (e.g. anti-oxidant, anti-carcinogenic, or anti-mutagenic and anti-inflammatory effects) and also contribute to their inducing apoptosis by arresting cell-cycle, regulating carcinogen metabolism and ontogenesis expression, inhibiting DNA binding and cell adhesion, migration, proliferation or differentiation, and blocking signaling pathways. A review by Huang et al., (2010) covers the most recent literature to summarize structural categories and molecular anti-cancer mechanisms of phenolic compounds from medicinal herbs and dietary plants (Huang, Cai, & Zhang., 2010).
Phenolics are compounds possessing one or more aromatic rings bearing one or more hydroxyl groups with over 8,000 structural variants, and generally are categorized as phenolic acids and analogs, flavonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and others based on the number of phenolic rings and of the structural elements that link these rings (Fresco et al., 2006).
Phenolic Acids
Phenolic acids are a major class of phenolic compounds, widely occurring in the plant kingdom. Predominant phenolic acids include hydroxybenzoic acids (e.g. gallic acid, p-hydroxybenzoic acid, protocatechuic acid, vanillic acid, and syringic acid) and hydroxycinnamic acids (e.g. ferulic acid, caffeic acid, p-coumaric acid, chlorogenic acid, and sinapic acid). Natural phenolic acids, either occurring in the free or conjugated forms, usually appear as esters or amides.
Due to their structural similarity, several other polyphenols are considered as phenolic acid analogs such as capsaicin, rosmarinic acid, gingerol, gossypol, paradol, tyrosol, hydroxytyrosol, ellagic acid, cynarin, and salvianolic acid B (Fresco et al., 2006; Han et al., 2007).
Gallic acid is widely distributed in medicinal herbs, such as Barringtonia racemosa, Cornus officinalis, Cassia auriculata, Polygonum aviculare, Punica granatum, Rheum officinale, Rhus chinensis, Sanguisorba officinalis, and Terminalia chebula as well as dietary spices, for example, thyme and clove. Other hydroxybenzoic acids are also ubiquitous in medicinal herbs and dietary plants (spices, fruits, vegetables).
For example, Dolichos biflorus, Feronia elephantum, and Paeonia lactiflora contain hydroxybenzoic acid; Cinnamomum cassia, Lawsonia inermis, dill, grape, and star anise possess protocatechuic acid; Foeniculum vulgare, Ipomoea turpethum, and Picrorhiza scrophulariiflora have vanillic acid; Ceratostigma willmottianum and sugarcane straw possess syringic acid (Cai et al., 2004; Shan et al., 2005; Sampietro & Vattuone, 2006; Stagos et al., 2006; Surveswaran et al., 2007).
Ferulic, caffeic, and p-coumaric acid are present in many medicinal herbs and dietary spices, fruits, vegetables, and grains (Cai et al., 2004). Wheat bran is a good source of ferulic acids. Free, soluble-conjugated, and bound ferulic acids in grains are present in the ratio of 0.1:1:100. Red fruits (blueberry, blackberry, chokeberry, strawberry, red raspberry, sweet cherry, sour cherry, elderberry, black currant, and red currant) are rich in hydroxycinnamic acids (caffeic, ferulic, p-coumaric acid) and p-hydroxybenzoic, ellagic acid, which contribute to their anti-oxidant activity (Jakobek et al., 2007).
Chlorogenic acids are the ester of caffeic acids and are the substrate for enzymatic oxidation leading to browning, particularly in apples and potatoes. Chlorogenic acid is a major phenolic acid from medicinal plants especially in the species of Apocynaceae and Asclepiadaceae (Huang et al., 2007).
Salvianolic acid B is a major water-soluble polyphenolic acid extracted from Radix salviae miltiorrhizae, which is a common herbal medicine clinically used as an anti-oxidant agent for thousands of years in China. There are 9 activated phenolic hydroxyl groups that may be responsible for the release of active hydrogen to block lipid peroxidation reaction. Rosmarinic acid is an anti-oxidant phenolic compound, which is found in many dietary spices such as mint, sweet basil, oregano, rosemary, sage, and thyme.
Gossypol, a polyphenolic aldehyde, derived from the seeds of the cotton plant (genus Gossypium, family Malvaceae), has contraceptive activity and can cause hypokalemia in some men. Gingerol, a phenolic substance, is responsible for the spicy taste of ginger.
Polyphenols
Polyphenols are a structural class of mainly natural, organic chemicals characterized by the presence of large multiples of phenol structural units. The number and characteristics of these phenol structures underlie the unique physical, chemical, and biological (metabolic, toxic, therapeutic, etc.) properties of particular members of the class. They may be broadly classified as phenolic acids, flavonoids, stilbenes, and lignans (Manach et al., 2004).
Initial evidence on cancer came from epidemiologic studies suggesting that a diet that includes regular consumption of fruits and vegetables (rich in polyphenols) significantly reduces the risk of many cancers.
Polyphenolic cancer action can be attributed not only to their ability to act as anti-oxidants but also to their ability to interact with basic cellular mechanisms. Such interactions include interference with membrane and intracellular receptors, modulation of signaling cascades, interaction with the basic enzymes involved in tumor promotion and metastasis, interaction with oncogenes and oncoproteins, and, finally, direct or indirect interactions with nucleic acids and nucleoproteins. These actions involve almost the whole spectrum of basic cellular machinery – from the cell membrane to signaling cytoplasmic molecules and to the major nuclear components – and provide insights into their beneficial health effects (Kampa et al., 2007).
Polyphenols and Copper
Anti-cancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as anti-oxidants, but can be pro-oxidants in the presence of copper ions. Through multiple assays, Khan et al. (2013) show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition.
Since the concentration of copper is significantly elevated in cancer cells, their results strengthen the idea that an important anti-cancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this pro-oxidant chemo-preventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.
IGF-1; Prostate Cancer
The ability of polyphenols from tomatoes and soy (genistein, quercetin, kaempferol, biochanin A, daidzein and rutin) were examined for their ability to modulate insulin-like growth factor-I (IGF-I)–induced in vitro proliferation and apoptotic resistance in the AT6.3 rat prostate cancer cell line. IGF-I at 50 µg/L in serum-free medium produced maximum proliferation and minimized apoptosis. Genistein, quercetin, kaempferol and biochanin A exhibited dose-dependent inhibition of growth with a 50% inhibitory concentration (IC50) between 25 and 40 µmol/L, whereas rutin and daidzein were less potent with an IC50 of >60 µmol/L. Genistein and kaempferol potently induced G2/M cell-cycle arrest.
Genistein, quercetin, kaempferol and biochanin A, but not daidzein and rutin, counteracted the anti-apoptotic effects of IGF-I. Human prostate epithelial cells grown in growth factor-supplemented medium were also sensitive to growth inhibition by polyphenols. Genistein, biochanin A, quercetin and kaempferol reduced the insulin receptor substrate-1 (IRS-1) content of AT6.3 cells and prevented the down-regulation of IGF-I receptor β in response to IGF-I binding.
Several polyphenols suppressed phosphorylation of AKT and ERK1/2, and more potently inhibited IRS-1 tyrosyl phosphorylation after IGF-I exposure. In summary, polyphenols from soy and tomato products may counteract the ability of IGF-I to stimulate proliferation and prevent apoptosis via inhibition of multiple intracellular signaling pathways involving tyrosine kinase activity (Wang et al., 2003).
Flavonoids
Flavonoids have been linked to reducing the risk of major chronic diseases including cancer because they have powerful anti-oxidant activities in vitro, being able to scavenge a wide range of reactive species (e.g. hydroxyl radicals, peroxyl radicals, hypochlorous acid, and superoxide radicals) (Hollman & Katan, 2000).
Flavonoids are a group of more than 4,000 phenolic compounds that occur naturally in plants (Ren et al., 2003). These compounds commonly have the basic skeleton of phenylbenzopyrone structure (C6-C3-C6) consisting of 2 aromatic rings (A and B rings) linked by 3 carbons that are usually in an oxygenated central pyran ring, or C ring (12). According to the saturation level and opening of the central pyran ring, they are categorized mainly into flavones (basic structure, B ring binds to the 2 position), flavonols (having a hydroxyl group at the 3 position), flavanones (dihydroflavones) and flavanonols (dihydroflavonols; 2–3 bond is saturated), flavanols (flavan-3-ols and flavan-3,4-diols; C-ring is 1-pyran), anthocyanins (anthocyanidins; C-ring is 1-pyran, and 1–2 and 3–4 bonds are unsaturated), chalcones (C-ring is opened), isoflavonoids (mainly isoflavones; B ring binds to the 3 position), neoflavonoids (B ring binds to the 4-position), and biflavonoids (dimer of flavones, flavonols, and flavanones) (Iwashina, 2000; Cai et al., 2004; Cai et al., 2006; Ren et al., 2003)
Tannins
Tannins are natural, water-soluble, polyphenolic compounds with molecular weight ranging from 500 to 4,000, usually classified into 2 classes: hydrolysable tannins (gallo- and ellagi-tannins) and condensed tannins (proanthocyanidins) (Cai et al., 2004).
The former are complex polyphenols, which can be degraded into sugars and phenolic acids through either pH changes or enzymatic or nonenzymatic hydrolysis. The basic units of hydrolysable tannins of the polyster type are gallic acid and its derivatives (Fresco et al., 2006). Tannins are commonly found combined with alkaloids, polysaccharides, and proteins, particularly the latter (Han et al., 2007).
Stilbenes
Stilbenes are phenolic compounds displaying 2 aromatic rings linked by an ethane bridge, structurally characterized by the presence of a 1,2-diarylethene nucleus with hydroxyls substituted on the aromatic rings. They are distributed in higher plants and exist in the form of oligomers and in monomeric form (e.g. resveratrol, oxyresveratrol) and as dimeric, trimeric, and polymeric stilbenes or as glycosides.
The well-known compound, trans-resveratrol, a phytoalexin produced by plants, is the member of this chemical famil most abundant in the human diet (especially rich in the skin of red grapes), possessing a trihydroxystilben skeleton (Han et al., 2007). There are monomeric stilbenes in 4 species of medicinal herbs, that is, trans-resveratrol in root of Polygonum cuspidatum, Polygonum multiflorum, and P. lactiflora; piceatannol in root of P. multiflorum; and oxyresveratrol in fruit of Morus alba (Cai et al., 2006).
It was reported that dimeric stilbenes and stilbene glycosides were identified from these species (Xiao et al., 2002). In addition, 40 stilbene oligomers were isolated from 6 medicinal plant species (Shorea hemsleyana, Vatica rassak, Vatica indica, Hopea utilis, Gnetum parvifolium, and Kobresia nepalensis). Other stilbenes that have recently been identified in dietary sources, such as piceatannol and its glucoside (usually named astringin) and pterostilbene, are also considered as potential chemo-preventive agents. These and other in vitro and in vivo studies provide a rationale in support of the use of stilbenes as phytoestrogens to protect against hormone-dependent tumors (Athar et al., 2007).
Curcuminoids
Curcuminoids are ferulic acid derivatives, which contain 2 ferulic acid molecules linked by a methylene with a β -diketone structure in a highly conjugated system. Curcuminoids and ginerol analogues are natural phenolic compounds from plants of the family Zingiberaceae. Curcuminoids include 3 main chemical compounds: curcumin, demethoxycurcumin, and bisdemethoxycurcumin (Cai et al., 2006). All 3 curcuminoids impart the characteristic yellow color to turmeric, particularly to its rhizome, and are also major yellow pigments of mustard. Curcuminoids containing Curcuma longa (turmeric) and ginerol analogues containing Zingiber officinale (ginger) are not only used as Chinese traditional medicines but also as natural color agents or ordinary spices.
In addition, curcuminoids with anti-oxidant properties have been isolated from various Curcuma or Zingiber species, such as the Indian medicinal herb Curcuma xanthorrhiza.
Coumarins
Coumarins are lactones obtained by cyclization of cis-ortho-hydroxycinnamic acid, belonging to the phenolics with the basic skeleton of C6+ C3. This precursor is formed through isomerization and hydroxylation of the structural analogs trans-hydroxycinnamic acid and derivatives. Coumarins are present in plants in the free form and as glycosides. In general, coumarins are characterized by great chemical diversity, mainly differing in the degree of oxygenation of their benzopyrane moiety.
In nature, most coumarins are C7-hydroxylated (Fresco et al., 2006; Cai et al., 2006). Major coumarin constituents included simple hydroxylcoumarins (e.g. aesculin, esculetin, scopoletin, and escopoletin), furocoumarins and isofurocoumarin (e.g. psoralen and isopsoralen from Psoralea corylifolia), pyranocoumarins (e.g. xanthyletin, xanthoxyletin, seselin, khellactone, praeuptorin A), bicoumarins, dihydro-isocoumarins (e.g. bergenin), and others (e.g. wedelolactone from Eclipta prostrata) (Shan et al., 2005).
Plants, fruits, vegetables, olive oil, and beverages (coffee, wine, and tea) are all dietary sources of coumarins; for example, seselin from fruit of Seseli indicum, khellactone from fruit of Ammi visnaga, and praeuptorin A from Peucedanum praeruptorum (Sonnenberg et al., 1995). In previous studies, it was found that coumarins occurred in the medicinal herbs Umbelliferae, Asteraceae, Convolvulaceae, Leguminosae, Magnoliaceae, Oleaceae, Rutaceae, and Ranunculaceae, such as simple coumarins from A. annua, furocoumarins (5-methoxyfuranocoumarin) from Angelica sinensis, pyranocoumarins from Citrus aurantium, and isocoumarins from Agrimonia pilosa. Coumarins have also been detected in some Indian medicinal plants (e.g. Toddalia aculeata, Murraya exotica, Foeniculum vulgare, and Carum copticum) and dietary spices (e.g. cumin and caraway). In addition, coumestans, derivatives of coumarin, including coumestrol, a phytoestrogen, are found in a variety of medicinal and dietary plants such as soybeans and Pueraria mirifica (Chansakaow et al., 2000).
Lignans
Lignans are also derived from cis-o-hydroxycinnamic acid and are dimers (with 2 C6-C3 units) resulting from tail–tail linkage of 2 coniferl or sinapyl alcohol units (Cai et al., 2007). Lignans are mainly present in plants in the free form and as glycosides in a few (Fresco et al., 2006). Main lignan constituents are lignanolides (e.g. arctigenin, arctiin, secoisolariciresinol, and matairesinol from Arctium lappa), cyclolignanolides (e.g. chinensin from Polygala tenuifolia), bisepoxylignans (e.g. forsythigenol and forsythin from Forsythia suspensa), neolignans (e.g. magnolol from Cedrus deodara and Magnolia officinalis), and others (e.g. schizandrins, schizatherins, and wulignan from Schisandra chinensis; pinoresinol from Pulsatilla chinensis; and furofuran lignans from Cuscuta chinensis) (Surveswaran et al., 2007).
The famous tumor therapy drug podophyllotoxin (cyclolignanolide) was first identified in Podophyllum peltatum, which Native Americans used to treat warts, and also found in a traditional medicinal plant Podophyllum emodi var. chinense (Efferth et al., 2007). Two new lignans (podophyllotoxin glycosides) were isolated from the Chinese medicinal plant, Sinopodophyllum emodi (Zhao et al., 2002). Different lignans (e.g. cubebin, hinokinin, yatein, and isoyatein) were identified from leaves, berries, and stalks of Piper cubeba L. (Piperaceae), an Indonesian medicinal plant (Elfahmi et al., 2007).
Milder et al. (2005) established a lignan database from Dutch plant foods by quantifying lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol in 83 solid foods and 26 beverages commonly consumed in The Netherlands. They reported that flaxseed (mainly secoisolariciresinol), sesame seeds, and Brassica vegetables (mainly pinoresinol and lariciresinol) contained unexpectedly high levels of lignans. Sesamol, sesamin, and their glucosides are also good examples of this type of compound, which comes from sesame oil and sunflower oil.
Quinones
Natural quinones in medicinal plants fall into 4 categories: anthraquinones, phenanthraquinones, naphthoquinones, and benzoquinones (Cai et al., 2004). Anthraquinones are the largest class of natural quinones and occur more widely in medicinal and dietary plants than other natural quinones (Cai et al., 2006). The hydroxyanthraquinones normally have 1 to 3 hydroxyl groups on the anthraquinone structure. Previous investigation found that quinones were distributed in 12 species of medicinal herbs from 9 families such as Polygalaceae, Rubiaceae, Boraginaceae, Labiatae, Leguminosae, Myrsinaceae, and so forth (Surveswaran et al., 2007).
For example, high content benzoquinones and derivatives (embelin, embelinol, embeliaribyl ester, embeliol) are found in Indian medicinal herb Embelia ribes; naphthoquinones (shikonin, alkannan, and acetylshikonin) come from Lithospermum erythrorhizon and juglone comes from Juglans regia; phenanthraquinones (tanshinone I, II A, and II B ) were detected in Salvia miltiorrhiza; denbinobin was detected in Dendrobium nobile; and many anthraquinones and their glycosides (e.g. rhein, emodin, chrysophanol, aloe-emodin, physcion, purpurin, pseudopurpurin, alizarin, munjistin, emodin-glucoside, emodin-malonyl-glucoside, etc.) were identified in the rhizomes and roots from P. cuspidatum (also in leaves), P. multiflorum, and R. officinale in the Polygalaceae and Rubia cordifolia in the Rubiaceae (Surveswaran et al., 2007; Huang et al., 2008). In addition, some naphthoquinones were isolated from maize (Zea mays L.) roots (Luthje et al., 1998).
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