期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 15, 期 46, 页码 12889-12899出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200901627
关键词
caffeic acid; cancer; chemoprevention; DNA damage; reaction mechanisms; reactive oxygen species
资金
- National Natural Science Foundation of China [20972063, 20621091]
- III Project
- Program for New Centurv Excellent Talents in University [NCET-06-0906]
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 Cull 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 Cut 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 Cull ions resulted in all 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 Cull 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.
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