Polyphenols and their therapeutic application in cancer

Polyphenols are a large family of 10,000 plant compounds that are known for their common structural features including the three-membered flavan ring system and multiple phenol units [10, 11]. These natural compounds are mostly found in fruits, green and black tea, coffee, red wine, cocoa, and seeds [12]. These beneficial organic agents are categorized into several subclasses including catechins, flavonoids (which contain flavonols, flavanols, and flavones), anthocyanins, catechins, isoflavones, chalcones, curcuminoids, and phenolic acids (structures are shown in Fig. 1) [12, 13].

Schematic representation of different structures of polyphenols. These agents have a three-membered flavan ring system in common

The idea of using polyphenols for treating cancer patients is not new. Early studies considering the anti-cancer effects of different polyphenols were conducted in the late twentieth century and our knowledge on these advantageous agents has been widely improved since then [14, 15]. What makes these agents greatly beneficial and interesting is that they attack cancer cells in a variety of ways and confront many cancer hallmarks (summarized in Fig. 2). Therefore, we shall briefly discuss different aspects of polyphenols’ effects in this section.

Some of the anti-cancer effects of polyphenols including epigenetic, anti-metastatic, pro-apoptotic, and anti-oxidant impacts Antioxidant effects The anti-oxidant impacts of polyphenols are possible through either scavenging free radicals or building a barrier against their generation. The main free radicals that exist in our cells and cause oxidative stress are reactive oxygen species (ROS) and reactive nitrogen species (RNS). The former mechanism of polyphenols’ action relies on the presence of benzene ring-bound hydroxyl groups which provide the ability to donate a hydrogen atom or an electron to free radicals. This occurrence stabilizes free radicals and prevents them from damaging the cellular components. It seems that the B ring of polyphenols plays the most important role in scavenging hydroxyl, peroxyl, and peroxynitrite radicals; however, the scavenging property can also be dependent on other structural parts in different polyphenols. For instance, in flavonoids, which are the best known polyphenols, a free 3-OH is mostly responsible for neutralizing the free radical. As mentioned above, polyphenols also have the capacity to inhibit the generation of ROS and RNS by interfering with the enzymes involved in their production. Nitric oxide synthases (NOS), xanthine oxidase (XO), and peroxidase are some of these enzymes, whose activity can be altered when certain interactions occur between them and polyphenols. Xanthine oxidase is one of the most important enzymes that generate superoxide from oxygen molecules. Quercetin, kaempferol, myricetin, and chrysin are among the polyphenols that are confirmed to inhibit this enzyme. NOS is also essential for producing nitric oxide in endothelial cells and macrophages. Nitric oxide mediates oxidative stress by increasing the production and concentration of peroxynitrite and thereby damaging the cellular membrane. Anthocyanidins are a subclass of polyphenols that prevent NOS from generating nitric oxide and thereby repressing their .NO scavenging capacity. Another production mechanism that is prone to be affected by the chelating properties of polyphenols is the metal-mediated reduction of peroxides. In this mechanism, which is known as the Fenton reaction, Fe2+ ions reduce H2O2 and thereby create a hydroxyl radical which is harmful to cells. In this concentration-dependent process, polyphenols can interfere as chelating agents and form stable complexes with iron. Inhibiting lipid peroxidation, removing iron from iron-loaded hepatocytes, blocking the Fenton reaction, and cellular protection are the results of the interactions between diverse polyphenols and iron.


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