nutrients Review Flavonoids as Anticancer Agents Dalia M. Kopustinskiene 1 , Valdas Jakstas 1,2 , Arunas Savickas 3 and Jurga Bernatoniene 1,3,* 1 Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; [email protected] (D.M.K.); [email protected] (V.J.) 2 Department of Pharmacognosy, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania 3 Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania; [email protected] * Correspondence: [email protected] Received: 29 January 2020; Accepted: 10 February 2020; Published: 12 February 2020 Abstract: Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine and cocoa-based products are the main dietary sources of flavonoids. Flavonoids have been shown to possess a wide variety of anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis, autophagy, and suppress cancer cell proliferation and invasiveness. Flavonoids have dual action regarding ROS homeostasis—they act as antioxidants under normal conditions and are potent pro-oxidants in cancer cells triggering the apoptotic pathways and downregulating pro-inflammatory signaling pathways. This article reviews the biochemical properties and bioavailability of flavonoids, their anticancer activity and its mechanisms of action. Keywords: flavonoids; cancer; ROS; antioxidants; pro-oxidants; mitochondria 1. Introduction Flavonoids are polyphenolic compounds synthesized in plants as bioactive secondary metabolites [1] responsible for their color, flavor and pharmacological activities [2]. The main flavonoid sources are fruits and vegetables [3], and they are also abundant in cocoa products (cocoa powder, chocolate) [4], black and green tea [3,5] and red wine [3,6]. Among the fruits, berries [7,8], plums, cherries [9,10] and apples [10,11] are the richest in flavonoids, whereas tropical fruits are poor in flavonoids [12]. Among the vegetables, the highest levels of flavonoids are found in broad beans [13], olives [14], onions [15], spinach [16] and shallot [17]. Flavonoids are potent antioxidants [11] protecting plants from unfavorable environmental conditions [1], therefore they have attracted attention and have been used in numerous epidemiological and experimental studies to assess their possible beneficial effects in multiple acute and chronic human disorders [18]. In vitro and in vivo studies have shown that flavonoids could exert anti-inflammatory, immunomodulatory [19] and strong anticancer activities [18,20,21]. 2. Chemical Properties of Flavonoids All flavonoids possess the basic flavan skeleton—a 15-carbon phenylpropanoid chain (C6-C3-C6 system), which forms two aromatic rings (A and B) linked by a heterocyclic pyran ring (C) (Figure1). Based on their chemical structure, degree of oxidation, and linking chain unsaturation flavonoids Nutrients 2020, 12, 457; doi:10.3390/nu12020457 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 457 2 of 24 Nutrients 2020, 12, 457 2 of 24 NutrientsNutrients 20202020, ,1212, ,457 457 2 2of of 24 25 could be further classified into 6 major groups: isoflavonoids, flavanones, flavanols, flavonols, could be further classified into 6 major groups: isoflavonoids, flavanones, flavanols, flavonols, couldflavones be andfurther anthocyanidins classified into [20,22,23]. 6 major groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins [20,22,23]. flavonescould be and further anthocyanidins classified into [20,22,23]. 6 major groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins [20,22,23]. FigureFigure 1.1. Main chemical structures ofof flavonoids.flavonoids. Figure 1. Main chemical structures of flavonoids. Figure 1. Main chemical structures of flavonoids. AA chromanechromane ringring (A(A andand C)C) isis attachedattached toto aa BB ringring (Figure(Figure1 )1) at at C2 C2 in in flavonoids flavonoids or or C3 C3 in in A chromane ring (A and C) is attached to a B ring (Figure 1) at C2 in flavonoids or C3 in isoflavonoidsisoflavonoidsA chromane [[22].22 ].ring TheThe (A mainmain and isoflavonoidsisoflavonoid C) is attacheds areare to genisteingenistein a B ring andand (Figure daidzeindaidzein 1) at(Figure(Figure C2 in2 2).). flavonoids or C3 in isoflavonoids [22]. The main isoflavonoids are genistein and daidzein (Figure 2). isoflavonoids [22]. The main isoflavonoids are genistein and daidzein (Figure 2). Figure 2. Chemical structures of the main isoflavonoids. Figure 2. Chemical structures of the main isoflavonoids. Figure 2. Chemical structures of the main isoflavonoids. A saturated, oxidizedFigure C ring 2. Chemical is present structures in flavanones, of the main also isoflavonoids. described as di-hydroflavones [22]. A saturated, oxidized C ring is present in flavanones, also described as di-hydroflavones [22]. MainA flavanones saturated, are oxidized hesperetin C ring and is naringenin present in (Figureflavanones,3)[22 also]. described as di-hydroflavones [22]. MainA flavanonessaturated, oxidizedare hesperetin C ring and is presentnaringenin in flavanones, (Figure 3) [22]. also described as di-hydroflavones [22]. Main flavanones are hesperetin and naringenin (Figure 3) [22]. Main flavanones are hesperetin and naringenin (Figure 3) [22]. Figure 3. Chemical structures of main flavanones. Figure 3. Chemical structures of main flavanones. Figure 3. Chemical structures of main flavanones. A saturated, unoxidizedFigure C ring 3. Chemical with a hydroxyl structures group of main at C3flavanones. is common for flavanols, also known as greenA saturated, tea catechins. unoxidized The most C ring common with a hydroxyl catechin group stereoisomers at C3 is common are cis ((-)-epicatechin)for flavanols, also or known trans A saturated, unoxidized C ring with a hydroxyl group at C3 is common for flavanols, also known ((as+ green)-catechinA saturated, tea catechins. according unoxidized The to C2 most C and ring common C3 with position a hydroxylcatechin in the stereoisomers group molecule at C3 [5, is24 are common,25 cis]. Flavanols ((-)-epicatechin) for flavanols, can form oralso gallictrans known acid((+)- as green tea catechins. The most common catechin stereoisomers are cis ((-)-epicatechin) or trans ((+)- as green tea catechins. The most common catechin stereoisomers are cis ((-)-epicatechin) or trans ((+)- Nutrients 2020, 12, 457 3 of 24 NutrientsNutrients 20202020,, 1212,, 457457 33 of 2524 catechin according to C2 and C3 position in the molecule [5,24,25]. Flavanols can form gallic acid catechin according to C2 and C3 position in the molecule [5,24,25]. Flavanols can form gallic acid conjugates epicatechin gallate, epigallocatechin and epigallocatechin gallate during esterification conjugatesconjugates epicatechinepicatechin gallate, gallate, epigallocatechin epigallocatechin and an epigallocatechind epigallocatechin gallate gallate during during esterification esterification with with gallate groups (Figure 4) [5,24,25]. gallatewith gallate groups groups (Figure (Figure4)[5,24 4),25 [5,24,25].]. Figure 4. Chemical structures of main flavanols. Figure 4. Chemical structures of main flavanols. Figure 4. Chemical structures of main flavanols. Flavonols possess an unsaturated C ring at the C2–C3 position, which is usually hydroxylated at Flavonols possess an unsaturated C ring at the C2–C3 position, which is usually hydroxylated C3 andFlavonols oxidized possess at C4 [ 22an]. unsaturated The main flavonols C ring at are the quercetin C2–C3 position, and kaempferol, which is followed usually hydroxylated by myricetin, at C3 and oxidized at C4 [22]. The main flavonols are quercetin and kaempferol, followed by isorhamnetin,at C3 and oxidized fisetin andat C4 galangin [22]. The found main in lesser flavonols amounts are (Figurequercetin5). Theand –OHkaempferol, moieties infollowed flavonols by myricetin, isorhamnetin, fisetin and galangin found in lesser amounts (Figure 5). The –OH moieties aremyricetin, responsible isorhamnetin, for their biological fisetin and activities. galangin found in lesser amounts (Figure 5). The –OH moieties in flavonols are responsible for their biological activities. in flavonols are responsible for their biological activities. Figure 5. Chemical structures of main flavonols. Figure 5. Chemical structures of main flavonols. Figure 5. Chemical structures of main flavonols. An unsaturated C ring at C2–C3, non-hydroxylated C3 and a ketonic group at C4 position are An unsaturated C ring at C2–C3, non-hydroxylated C3 and a ketonic group at C4 position are presentAn in unsaturated flavones [22 C]. Thering mainat C2–C3, flavones non-hydroxylated include apigenin, C3 chrysin, and a ketonic luteolin, group and tangeritin at C4 position (Figure are6). present in flavones [22]. The main flavones include apigenin, chrysin, luteolin, and tangeritin (Figure present in flavones [22]. The main flavones include apigenin, chrysin, luteolin, and tangeritin (Figure 6). 6). Nutrients 2020, 12, 457 4 of 24 Nutrients 2020, 12, 457 44 of of 24 25 FigureFigure 6. 6.Chemical Chemical structures structures of of main main flavones. flavones.