Plant polyphenols mobilize endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: A putative mechanism for anticancer properties

Azmi, Asfar S.; Bhat, Ramesa Shafi; Hanif, Sarmad; Hadi, S. M.

doi:10.1016/j.febslet.2005.12.059

Cited by 161 publications

(123 citation statements)

References 31 publications

(53 reference statements)

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“…The involvement of ROS has been proposed as upstream event occurring during treatment with high (micro-molar) concentrations of trans-resveratrol [1,21], as well as with other polyphenols, including epigallocatechin-3-gallate [44,53), woodfordin I [35] and quercetin [33,64]. In our experimental system ROS burst occurs precociously (within the first hour) and the detrimental effects produced were confirmed by the increase in lipid peroxidation by-products, MDA and 4-HNE.…”

Section: Trans-resveratrol Induce a Selective Activation Of Jnk And Pmentioning

confidence: 77%

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

et al. 2007

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Polyphenols represent a large class of plantderived molecules with a general chemical structure that act as potent free radical scavengers. They have long been recognized to possess several therapeutic activities ranging from anti-thrombotic to antioxidant. Moreover, the capability of polyphenols to act as reducing or oxidizing molecules depends on the presence of environmental metals and on the concentrations used. In this work we demonstrated that the stilbene trans-resveratrol was able to commit human breast cancer MCF-7 cells to apoptosis. Mainly, we evidenced a pivotal role of the mitochondria in this phenomenon as cytochrome c release into the cytosol was found after the treatment. We further showed that trans-resveratrol was able to affect cellular redox state. In particular, it induced an early production of ROS and lipid oxidation, and only later compromised the GSH/GSSG ratio. This mode of action was mirrored by a temporally different activation of JNK and p38 MAPK , with the former rapidly induced and the latter weakly activated at long intervals. The results obtained demonstrate a pro-apoptotic activity for trans-resveratrol, and suggest a preferential activation of different classes of MAP kinases in response to different oxidative stimuli (ROS versus GSH/GSSG alteration).

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Section: Trans-resveratrol Induce a Selective Activation Of Jnk And Pmentioning

confidence: 77%

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

et al. 2007

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“…25 These data are confirmed by many authors using doses comparable to those used in our article. 26 The pro-oxidant action which involves the mobilization of endogenous copper could be a common mechanism for anticancer and chemopreventive properties of plant polyphenols. These results are also consistent with what is well known about other polyphenols which have both anti-and pro-oxidant activity 27 and inhibit topoisomerase II activity depending on concentrations, duration and mode of treatment, cell types.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol acts as a topoisomerase II poison in human glioma cells

Leone

Basso

Polticelli

et al. 2012

Intl Journal of Cancer

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Recently, we demonstrated that Resveratrol (RSV), a well known natural stilbene, is able to induce a delay in S progression with a concomitant increase in cH2AX expression in U87 glioma cells. Furthermore, we showed that it inhibits the ability of recombinant human topoisomerase IIa to decatenate kDNA in vitro. Because proliferating tumor cells express topoisomerases at high levels and these enzymes are important targets of some of the most successful anticancer drugs, we tested whether RSV is able to poison topoisomerase IIa in glioma cells. Then, we monitored the increase of micronuclei in RSV treated U87 cells as a consequence of the conversion of TOPOII/DNA cleavable complexes to permanent DNA damage. Finally, we assayed the ability of RSV in modulating the expression of target proteins involved in DNA damage signalling, namely ATR, ATM, Chk1, Chk2 and cH2AX. Through a molecular modelling here we show that RSV binds at the TOPOII/DNA interface thus establishing several hydrogen bonds. Moreover, we show that RSV poisons TOPOIIa so inducing DNA damage; ATM, Chk2 and cH2AX are involved in the DNA damage signalling after RSV treatment.Resveratrol (3,4 0 ,5-trihydroxylstilbene), a polyphenol synthesized by a wide variety of plant species, is well known for its antitumor potential as demonstrated by many in vitro studies. 1 Nevertheless, the molecular targets of Resveratrol (RSV) activity seem not yet completely understood due to the multiplicity of RSV treatment effects in normal and transformed cultured cells. However, it is well known that RSV can disturb the normal progress of the cell cycle so decreasing the proliferation and can also induce apoptosis in cell type-and concentration-dependent mode. 2 On the other hand RSV, such as many other natural polyphenols, acts as antioxidant or prooxidant due to the intracellular presence of transition metal ions. The prooxidant activity could be an important action mechanism for its anticancer properties. 3 It has been suggested that some of the cellular effects of polyphenols, such as anti-proliferative and proapoptotic actions, could be correlated with their ability to act on topoisomerases. 4,5 These are ubiquitous nuclear enzymes that modulate the topological state of DNA by breaking and resealing one or both strands of a DNA duplex. In eukaryotic cells, type II topoisomerases, isoforms a and b, function during major cellular processes involving DNA (recombination, replication, proper chromosome structure and segregation) generating intermediate cleavable or covalent complexes with a short half-life. 6 Highly proliferating tumor cells express these enzymes, particularly Type IIa, at levels many times higher than quiescent cells 7,8 so that topoisomerases II are important targets for some of the anticancer drugs most successfully used in the treatment of human malignancies. TOPOII-targeted agents interfere with the binding between DNA and TOPOII or act by increasing the concentration of topoisomerase-DNA covalent complexes. These agents shifting the equilibrium of t...

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“…In addition to their antioxidant properties, it is worthy to note that cytotoxic effects of RES, PIC, and TPS have also been reported. In this regard, RES has demonstrated pro-oxidant, genitourinary, immunotoxic, hepatotoxic and genotoxic properties [18][19][20][21][22][23]. PIC, a metabolite of RES, has been reported to induce apoptosis of transformed and primary lymphocytes [17] and to also exhibit cytotoxic actions towards macrophages in vitro [24].…”

Section: Introductionmentioning

confidence: 99%

In Vitro evaluation of the cytotoxic and anti-proliferative properties of resveratrol and several of its analogs

Billack¹,

Radkar²,

Adiabouah³

2008

Cellular and Molecular Biology Letters

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Resveratrol (RES), a component of red wine, possesses antiinflammatory properties. The studies described in the present work were aimed at evaluating the potential for RES and related stilbene analogs (piceatannol, PIC; pterostilbene, TPS; trans-stilbene, TS; and trans-stilbene oxide, TSO) to exhibit toxicity towards RAW 264.7 mouse macrophages. The effect of TS, TSO, RES and TPS on RAW 264.7 macrophage viability was determined by two standard methods: (a) the MTT assay and (b) the trypan blue dye exclusion test. Whereas macrophages were more sensitive to PIC (LC 50 trypan ~ 1.3 μM) and to TPS (LC 50 trypan ~ 4.0 μM and LC 50 MTT ~ 8.3 μM) than to RES (LC 50 trypan ~ 8.9 μM and LC 50 MTT ~ 29.0 μM), they were relatively resistant to TSO (LC 50 trypan ~ 61.0 μM and LC 50 MTT > 100 μM) and to TS (LC 50 trypan ≥ 5.0 μM and LC 50 MTT ≥ 5.0 μM). The ability of selected stilbenes (RES, TPS and PIC) to exhibit growth inhibitory effects was also examined. Although RES and TPS were observed to inhibit cell proliferation in macrophages (IC 50 ≤ 25 µM), these cells were resistant to growth inhibition by PIC (IC 50 ≥ 50 µM). The data obtained in the present analysis demonstrate that substituted stilbene compounds such as RES have the capacity to exhibit cytotoxic and anti-proliferative activities in macrophages.

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Plant polyphenols mobilize endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: A putative mechanism for anticancer properties

Cited by 161 publications

References 31 publications

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

Resveratrol acts as a topoisomerase II poison in human glioma cells

In Vitro evaluation of the cytotoxic and anti-proliferative properties of resveratrol and several of its analogs

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