Hydroxycinnamic acids as DNA-cleaving agents in the presence of Cu(II) ions: mechanism, structure-activity relationship, and biological implications.
The effectiveness of hydroxycinnamic acids (HCAs), that is, caffeic acid (CaA), chlorogenic acid (ChA), sinapic acid (SA), ferulic acid (FA), 3-hydroxycinnamic acid (3-HCA), and 4-hydroxycinnamic acid (4-HCA), as pBR322 plasmid DNA-cleaving agents in the presence of Cu(II) ions was investigated. Compounds bearing o-hydroxy or 3,5-dimethoxy groups on phenolic rings (CaA, SA, and ChA) were remarkably more effective at causing DNA damage than the compounds bearing no such groups; furthermore, CaA was the most active among the HCAs examined. The involvement of reactive oxygen species (ROS) and Cu(I) ions in the DNA damage was affirmed by the inhibition of the DNA breakage by using specific scavengers of ROS and a Cu(I) chelator. The interaction between CaA and Cu(II) ions and the influence of ethylenediaminetetraacetic acid (EDTA), the solvent, and pH value on the interaction were also studied to help elucidate the detailed prooxidant mechanism by using UV/Vis spectroscopic analysis. On the basis of these observations, it is proposed that it is the CaA phenolate anion, instead of the parent molecule, that chelates with the Cu(II) ion as a bidentate ligand, hence facilitating the intramolecular electron transfer to form the corresponding CaA semiquinone radical intermediate. The latter undergoes a second electron transfer with oxygen to form the corresponding o-quinone and a superoxide, which play a pivotal role in the DNA damage. The intermediacy of the semiquinone radical was supported by isolation of its dimer from the Cu(II)-mediated oxidation products. Intriguingly, CaA was also the most cytotoxic compound among the HCAs toward human promyelocytic leukemia (HL-60) cell proliferation. Addition of exogenous Cu(II) ions resulted in an effect dichotomy on cell viability depending on the concentration of CaA; that is, low concentrations of CaA enhanced the cell viability and, conversely, high concentrations of CaA almost completely inhibited the cell proliferation. On the other hand, when superoxide dismutase was added before, the two stimulation effects of exogenous Cu(II) ions were significantly ameliorated, thus clearly indicating that the oxidative-stress level regulates cell proliferation and death. These findings provide direct evidence for the antioxidant/prooxidant mechanism of cancer chemoprevention.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China.
Gui-Juan
GJ
Fan
Xiao-Ling
XL
Jin
Yi-Ping
YP
Qian
Qi
Q
Wang
Ru-Ting
RT
Yang
Fang
F
Dai
Jiang-Jiang
JJ
Tang
Ya-Jing
YJ
Shang
Li-Xia
LX
Cheng
Jie
J
Yang
Bo
B
Zhou
D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D003373:Coumaric Acids / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D053960:DNA Breaks / Q000187:drug effects; D004492:Edetic Acid / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D003373:Coumaric Acids; D017382:Reactive Oxygen Species; D012997:Solvents; D003300:Copper; D004247:DNA; D004492:Edetic Acid