Caffeic Acid Phenyl Ester (CAPE) Protects against Iron-Mediated Cellular DNA Damage through Its Strong Iron-Binding Ability and High Lipophilicity

Abstract

Caffeic acid phenethyl ester (CAPE) and its structurally-related caffeic acid (CA), ferulic acid (FA) and ethyl ferulate (EF) are constituents of honeybee propolis that have important pharmacological activities. This study found that CAPE—but not CA, FA, and EF—could effectively prevent cellular DNA damage induced by overloaded iron through decreasing the labile iron pool (LIP) levels in HeLa cells. Interestingly, CAPE was found to be more effective than CA in protecting against plasmid DNA damage induced by Fe(II)–H2O2 or Fe(III)–citrate–ascorbate-H2O2 via the inhibition of hydroxyl radical (•OH) production. We further provided more direct and unequivocal experimental evidences for the formation of inactive CAPE/CA–iron complexes. CAPE was found to have a stronger iron-binding ability and a much higher lipophilicity than CA. Taken together, we propose that the esterification of the carboxylic moiety with phenethyl significantly enhanced the iron-binding ability and lipophilicity of CAPE, which is also responsible for its potent protection against iron-mediated cellular DNA damage. A study on the iron coordination mechanism of such natural polyphenol antioxidants will help to design more effective antioxidants for the treatment and prevention of diseases caused by metal-induced oxidative stress, as well as help to understand the structure–activity relationships of these compounds.

Chain-Breaking Antioxidant and Peroxyl Radical Trapping Activity of Phenol-Coated Magnetic Iron Oxide Nanoparticles

“…The fact that MAG-NDGA has a reactivity similar to that of the other SPION suggests that both catechol groups of NDGA are involved in binding to the metal surface. Interestingly, the phenol-capped SPION do not have the same pro-oxidant effects as bare SPION, most likely because the phenol-bound iron ions are no longer active, in agreement with the known Fenton-suppressing effect of polyphenolic iron chelators [ 45 ]. Moreover, it cannot be excluded that, although the heterogeneous Fenton reaction was not entirely suppressed, the alkoxyl radicals, being extremely reactive [ 46 ], may react with the capping phenols.…”

New Deferric Amine Compounds Efficiently Chelate Excess Iron to Treat Iron Overload Disorders and to Prevent Ferroptosis

“…The higher lipophilicity of DFAs could facilitate their transport across the plasma membrane, where they could exhibit the iron‐chelating ability inside the cell. [ 20 ]…”

“…IC50 was defined as the 50% inhibitory concentration of each ligand. The binding constants between each ligand and Fe (III) were calculated with the following equation: [ 20 , 39 ] where the (probe) is the concentration of calcein at 1 µ m , and the intrinsic calcein‐binding constant of Fe(III), K b(Fe(III)‐calcein) is 10 24 m –1 . K probe(calcein) is the dissociation constant for the intercalation of Fe(III) with calcein, and K probe (calcein) is 1/10 24 m .…”

“…IC50 was defined as the 50% inhibitory concentration of each ligand. The binding constants between each ligand and Fe (III) were calculated with the following equation: [20,39]…”

Caffeic Acid Prevents Vascular Oxidative Stress and Atherosclerosis against Atherosclerogenic Diet in Rats

“…CA occurs in fruits, olives, coffee beans, grains, propolis, and many dietary supplements [ 18 ]. Furthermore, CA has free-radical-scavenging and metal ion-chelating properties and can also fortify endogenous antioxidants that form the basis of detoxifying mechanisms in the body [ 19 ]. CA targets several signaling pathways (e.g., p38 MAPK, transcription factor and signal translation 3, metallopeptidase, nuclear factor kappa B, and adhesion molecules) and molecular mechanisms (e.g., nitric oxide, 5-lipoxygenase, calcium, potassium channels, and adrenergic receptors) associated with oxidative stress, inflammation, and immunomodulation that may modify the pathogenesis of hypercholesterolemia and CVDs [ 17 , 20 ].…”