Original ContributionDNA damage induced by resveratrol and its synthetic analogues in the presence of Cu (II) ions: Mechanism and structure-activity relationship
Introduction
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin present in grapes, nuts, and other plants. It is believed that the high level of this compound in red wine (0.1–15 mg/L) [1] is linked to the low incidence of heart diseases in some regions of France, the so-called “French paradox;” i.e., despite high fat intake, mortality from coronary heart disease is lower due to the regular drinking of wine [2], [3]. In addition, resveratrol has been shown to possess cancer chemopreventive activity [4], [5], [6], [7]. The metabolism and bioavailability of resveratrol have been studied in detail recently [8]. Therefore, the past several years have witnessed intense research devoted to the biological activity, especially the antioxidative activity, of this compound [9], [10], [11], [12], since free radical-induced oxidative damage of cell membranes, DNA, and protein is considered to play a causative role in aging and several degenerative diseases, such as cancer and atherosclerosis [13], [14], [15], [16]. On the other hand, it was reported that an antioxidant might become a prooxidant to accelerate lipid peroxidation and/or induce DNA damage under special conditions [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. α-Tocopherol (vitamin E), a well-known antioxidant, was reported to be able to accelerate low-density lipoprotein (LDL) peroxidation via the tocopherol-mediated peroxidation (TMP) [17], [18], and to induce DNA damage in the presence of cupric ions [19]. Other polyphenolic antioxidants, including quercetin [20], curcumin [21], tea cathechins [22], salsolinol [23], and resveratrol [24], [25], [26], [27], were also reported to induce lipid peroxidation and/or DNA damage in the presence of cupric ions. Therefore, it is of interest to see how an antioxidant can switch to a prooxidant and its biological implication.
We found recently that some synthetic resveratrol analogues bearing ortho-diphenoxyl functionality exhibit significantly higher antioxidant and cytotoxic activity against HL-60 cancer cells than resveratrol and other analogues bearing no such functionality [28], [29], [30], [31]. It was reported very recently that resveratrol and other polyphenols could mobilize endogenous copper in human peripheral lymphocytes, leading to oxidative DNA breakage that might be responsible for their anticancer properties [32]. These observations motivated us to study the Cu (II)-mediated oxidative DNA damage by resveratrol and its analogues, putting emphasis on the structure-activity relationship and the mechanism of the prooxidant activity of these compounds. The compounds (ArOH) studied are 3,5,4′-trihydroxy-trans-stibene (resveratrol), 3,4,4′-trihydroxy-trans-stibene (3,4,4′-THS), 3,4,5-trihydroxy-trans-stibene (3,4,5-THS), 3,4-dihydroxy-trans-stibene (3,4-DHS), 4,4′-dihydroxy-trans-stibene (4,4′-DHS), 2,4-dihydroxy-trans-stilbene (2,4-DHS), 3,5-dihydroxy-trans-stilbene (3,5-DHS), and 3,5,4′-trimethoxy-trans-stibene (3,5,4′-TMS).
Molecular Structure
Section snippets
Materials
Resveratrol and its analogues, i.e., 3,4,4′-THS, 3,4,5-THS, 3,4-DHS, 4,4′-DHS, 2,4-DHS, 3,5-DHS, and 3,4,5-TMS were synthesized with reference to the modified Wittig reaction [33], [34] using diethylbenzylphosphonate, which was prepared from methoxyl-substituted benzyl chloride and triethyl phosphate, reacted with methoxyl substituted benzaldehyde, and followed by removing the methyl protecting group with pyridine hydrochloride. This procedure gave exclusively the trans-isomers with moderate to
Strand breakage of plasmid pBR322 DNA induced by resveratrol and its analogues in the presence of Cu (II)
The destruction of the supercoiled pBR322 DNA and formation of the open circular and linear forms of DNA were used to assess the DNA strand breakage [35]. It was found that neither resveratrol nor Cu (II) alone with concentrations up to 200-300 μM showed appreciable effect on the DNA (Lanes 2 and 3 in Fig. 1, Fig. 2, respectively). Other resveratrol analogues (ArOH) also did not induce the DNA strand breakage in the absence of Cu (II) (Fig. 3). However, Cu (II) could work cooperatively with
Discussion
The resveratrol–Cu (II)-induced oxidative DNA damage has been studied by many investigators previously [9], [24], [25], [26], [27], [35]. However, the structural basis for its activity and the relationship between the antioxidant and the prooxidant activity, as well as cytotoxicity of this molecule, have scarcely been exploited [10], [27]. The present work studied the prooxidant activity of eight resveratrol analogues (ArOH) with three different structural features that enables us to deduce a
Acknowledgments
We thank the National Natural Science Foundation of China (Grant Nos. 20502010, 20332020, and 20021001) for financial support.
References (56)
- et al.
Resveratrol: a molecule whose time has come? And gone?
Clin. Biochem.
(1997) - et al.
Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets
Mutat. Res.
(2004) - et al.
Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action
Arch. Biochem. Biophys.
(2000) - et al.
Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure-activity ralationship
Biochem. Pharmacol.
(2005) - et al.
The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury
Free Radic. Biol. Med.
(1999) - et al.
Mechanism of oxidative DNA damage induced by quercetin in the presence of Cu (II)
Mutat. Res.
(1999) - et al.
Strand scission in DNA induced by curcumin in the presence of Cu(II)
Cancer Lett.
(1998) - et al.
DNA cleavage reaction and linoleic acid peroxidation induced by tea catechins in the presence of cupric ion
Biochim. Biophys. Acta
(1997) - et al.
Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid
Free Radic. Biol. Med.
(2001) - et al.
Resveratrol as a new type of DNA-cleaving agent
Bioorg. Med. Chem. Lett.
(1998)
DNA breakage by resveratrol and Cu (II): reaction mechanism and bacteriophage inactivation
Cancer Lett.
Resveratrol–Cu(II) induced DNA breakage in human peripheral lymphocytes: implications for anticancer properties
FEBS Lett.
Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II)
Bioorg. Med. Chem.
Inhibition of free radical-induced peroxidation of rat liver microsomes by resveratrol and its analogues
Biochim. Biophys. Acta
Structure-activity relationship studies of resveratrol and its analogues by the reaction kinetics of low density lipoprotein peroxidation
Bioorg. Chem.
Plant polyphenols mobilize endogeneous copper in human peripheral lymphocytes leading to oxidative DNA breakage: a putative mechanism for anticancer properties
FEBS Lett.
Different effects of genistein and resveratrol on oxidative DNA damage in vitro
Mutat. Res.
Copper-catalyzed DNA damage by ascorbate and hydrogen peroxide: kinetics and yield
Free Radic. Biol. Med.
Protective role of zinc-metallothionein on DNA damage in vitro by ferric nitrilotriacetate (Fe-NTA) and ferric salts
Chem. Biol. Interact.
Protective effects of flavonols and their glycosides against free radical-induced oxidative hemolysis of red blood cells
Life Sci.
Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy-3-methoxyphenyl groups
Free Radic. Biol. Med.
Inhibition of lipid peroxidation and protein oxidation in rat liver mitochondria by curcumin and its analogues
Biochim. Biophys. Acta
Proteasome-independent down-requlation of estrogen receptor-α (ERα) in breast cancer cells treated with 4,4′-dihydroxy-trans-stilbene
Biochem. Pharmacol.
Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties
Free Radic. Biol. Med.
Relationship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma
J. Hepatol.
Biological effects of resveratrol
Life Sci.
Endothelin-1 synthesis reduced by red wine
Nature
Cancer chemopreventive activity of resveratrol, a natural product derived from grapes
Science
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