Flavonoids as Anticancer Agents

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: ROS; antioxidants; cancer; flavonoids; mitochondria; pro-oxidants.

Figure 1

Main chemical structures of flavonoids.

Figure 2

Chemical structures of the main isoflavonoids.

Figure 3

Chemical structures of main flavanones.

Figure 4

Chemical structures of main flavanols.

Figure 5

Chemical structures of main flavonols.

Figure 6

Chemical structures of main flavones.

Figure 7

Chemical structures of main anthocyanidins.

Figure 8

The main characteristics of tumor mitochondria and tumor cells.

Figure 9

Antioxidant and pro-oxidant activities of flavonoids in oxidative stress. ROS—reactive oxygen species, NADPH-oxidase—nicotinamide adenine dinucleotide phosphate oxidase, GSH—glutathione, SOD—superoxide dismutase, CAT—catalase, GPx—glutathione peroxidase, GR—glutathione reductase.

Figure 10

Flavonoid targets in extrinsic and intrinsic apoptosis pathways. TNF—tumor necrosis factor, tBid—truncated Bid, Bcl-2—B-cell lymphoma protein 2, Bcl-xL—Bcl-2 homologue splice variants, Cyt c—cytochrome c, SMAC—second mitochondrial activator of caspases, IAPs—inhibitor of apoptosis proteins, APAF-1—apoptotic protease activating factor 1. Yellow arrows show the effect of flavonoids (activation or suppression).

Figure 11

Flavonoid targets during inflammation processes. TNF—tumor necrosis factor, IL—interleukin, AP-1—activator protein 1, NF-κB—nuclear factor kappa-light- chain-enhancer of activated B cells, STAT3—signal transducer and activator 3, NOX—NADPH oxidase, COX-2—cyclooxygenase-2, iNOS—inducible nitric oxide synthase, AMPK—AMP—activated protein kinase, PI3K—phosphatidylinositide 3-kinases, Akt—protein kinase B, mTOR—mammalian target of rapamycin, MAPK—mitogen activated protein kinase, ERK—extracellular-signal-regulated kinase, JNK—c-Jun N-terminal kinase, p38—p38 kinse, IκB—IκB kinase, JAK—Janus kinase.

Figure 12

Indirect and direct effects of flavonoids on mitochondrial functions.