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DOI: 10.1055/s-0032-1315020
Effects of Curcumin on Nitrosyl-Iron Complex – Mediated DNA Cleavage and Cytotoxicity
Correspondence
Publication History
received 25 April 2012
accepted 07 June 2012
Publication Date:
06 July 2012 (online)
Abstract
Combination therapy aims to improve the pharmaceutical efficacy of different drugs, thus lowering the dosages used and reducing the side effects. However, interactions between individual drugs may also occur and lead to uncertain consequences. This study demonstrated that curcumin, a natural phenolic compound found in the rhizomes of turmeric, could either inhibit or enhance DNA cleavage caused by the synthetic nitrosyl-iron complex NC10 ([Fe2(C2H5OS)2(NO)4]). Without UV irradiation, higher concentrations of curcumin protected DNA from being cleaved by NC10. Conversely, in the presence of lower concentrations of curcumin (< 5 µM), cleaved DNA increased by raising curcumin concentrations. After UV irradiation, the DNA protective effect of curcumin decreased while the enhancing DNA cleavage effect of curcumin remained. UV/visible spectroscopy analysis showed that curcumin is associated with the iron of NC10, suggesting the formation of curcumin-Fe complexes. Furthermore, a cytotoxicity assay revealed that cotreatment of NC10 and curcumin had synergetic effects on the growth inhibition of mouse melanoma B16-F10 cells. To our knowledge, this is the first study of the cotreatment of curcumin with inorganic compounds that showed synergistic cytotoxicity.
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Key words
curcumin - Curcuma longa - Zingiberaceae - cytotoxicity - DNA cleavage - metal-nitrosyl complexesIntroduction
Nitric oxide (NO) acts as a lethal free radical. NO reacts with O2 or O2 − to form NO2 and NO3 −. These free radicals can damage lipids, DNA, and proteins, resulting in cell death [1], [2], [3]. To avoid damage caused by NO, organisms convert NO into more stable forms for storage and transportation. Two pathways for reducing NO residuals exist in vivo. One pathway is to transfer NO into NO+ by binding to cysteine or glutathione. Formation of S-nitrosothiol (RS-NO) can further stabilize NO residuals [4], [5]. The other pathway is to form dinitrosyl-iron complexes (DNIC) by binding NO with irons and other ligands such as cysteine, histidine, GSH, or water molecules [6], [7]. These naturally occurring NO complexes have inspired synthetic chemists to design and synthesize novel NO carriers.
The highly reactive properties of NO hold pharmaceutical potential that could be used to fight cancer. In mammals, NO is produced by several NO synthesis enzymes, including iNOs [8], [9], [10]. Studies have shown that the deletion of iNOs can promote tumor growth in certain types of cancer, suggesting that NO could inhibit cancer growth [11], [12]. Moreover, in vitro studies have shown that high concentrations of NO (> 300 nM) increase phosphorylation and nitrosylation of enzymes, consequently leading to apoptosis [7]. Several synthetic NO carriers such as nitrobenzene derivatives and Roussinʼs black salt have recently been tested in cancer treatments [13]. In addition to releasing NO spontaneously, photochemically active NO-release compounds have been developed [14], [15]. Another improvement is to increase the water solubility of synthetic NO donors. Several water-soluble DNIC and RREs have been synthesized and their cytotoxicity to cancer cells has been demonstrated [16], [17], [18].
Despite inhibiting the growth of cancer cells, exposure to lower NO concentrations (1–100 nM) increases angiogenesis and proliferation of endothelial cells [19]. Moreover, it also enhances the activity of anti-apoptotic genes in tumors and protects the tumor cell from apoptosis [20], [21], [22], [23]. These undesired side effects should be considered when using NO carriers, in particular photochemically active NO-release compounds, for treatment. Because treated cancer cells outside the irradiation zone or that are buried deeper in the tumors may receive inefficient amounts of light energy and result in only small amounts of NO release, cancer cell growth could be promoted.
Curcumin is a well-known free radical scavenger originally identified from the rhizomes of turmeric (Curcuma longa, Zingiberaceae). The chemical structure of curcumin is 1,7-bis-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione ([Fig. 1]). Curcumin is used as an herbal medicine in Asian countries for the treatment of abdominal spasm, diarrhea, fever, headache, and vomiting [24]. Recent studies have demonstrated that curcumin also has antioxidant [25], [26], [27], antitumor [28], and anti-inflammatory activities [29]. Curcumin also displays lethal toxicity to bacteria [30], [31], parasites [32], [33], and zebrafish [34]. Although the mechanisms of curcumin-mediated cell death have been studied in detail, clinical applications of curcumin are limited because of its low bioavailability. Curcumin is water insoluble and easily decomposes after exposure to light or an alkaline pH [24]. Animal studies showed that only minimal orally administered curcumin can be absorbed, with the rest excreted in the feces [35], [36]. Several strategies, including synthetic analogs, new formulations, and combinations with other components, have been applied to overcome these deficiencies [37], [38], [39].
We were interested in investigating whether nitrosyl-iron complexes have synergistic cytotoxicity effects in cotreatments with curcumin. The goal was not only to improve the pharmaceutical efficacy of both nitrosyl-iron complexes and curcumin, but also to prevent cells from receiving low concentrations of NO because of curcuminʼs NO scavenging activity. Our previous study showed no synergistic cytotoxicity effect in treatments combining curcumin with DNICs (i.e., NC01, 02, and 03) synthesized by our laboratory. However, we found that pretreatment of curcumin followed by treatment of NC03 resulted in additive cytotoxicity effects [40]. This encouraged us to develop new NO carriers for use in the cotreatment with curcumin. In this report, we demonstrated that curcumin could manipulate the DNA cleavage mediated by a newly synthesized RRE, named NC10. We also showed that cotreatment of curcumin with NC10 exerted synergistic cytotoxicity against mouse melanoma B16-F10 cells in vitro.
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Materials and Methods
Chemicals
The synthesis of NC10 was described in a previous study; its purity was 99.9 % [41]. The structure of NC10 is shown in [Fig. 1]. Curcumin (> 80 % curcumin, > 94 % curcuminoid content), dimethyl sulfoxide (DMSO) and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) were purchased from Sigma-Aldrich Co. Dulbeccoʼs modified Eagleʼs medium (DMEM), fetal bovine serum (FBS), phosphate-buffered saline (PBS), penicillin, streptomycin, and trypsin–EDTA were all purchased from Gibco BRL.
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Plasmid DNA cleavage
The self-ligated pGEM-T vector was purified from DH5α and used in the DNA cleavage assays. The reaction mixtures contained 50 ng plasmid DNA, 10 µL reaction buffer (10 mM Tris-HCl, pH 7.4), and selective concentrations of NC10, curcumin, or combinations of NC10 and curcumin. The reactions were conducted by placing the reaction mixtures in the dark or exposing them to UV light of 302 nm for 3 min or 5 min. When the incubation was complete, the reactions were terminated by adding 1 µL KCN (1 M) and 1 µL EDTA (0.04 M), and incubating at 60 °C for 30 min. The supercoiled, nicked circular, and linear plasmid DNA fragments were separated on a 1 % agarose gel by electrophoresis. The gels were stained with ethidium bromide and the images of the stained gels were photographed by a digital camera under UV light.
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Infrared and UV-visible spectroscopes
The association between curcumin and NC10 was detected by infrared and UV-visible spectrometry. The solutions of 30 mM NC10 alone or in combination with selective concentrations of curcumin (30 mM, 60 mM, 90 mM, 120 mM, 150 mM) were freshly prepared using THF as the solvent. After UV exposure for 3 min, the solutions were sealed in cells (0.1 mm, KBr windows), and scanned using a Perkin Elmer model Spectrum One B spectrometer. For UV-visible spectra, the solutions of 30 µM curcumin, 15 µM NC10, or a combination of 30 µM curcumin and 15 µM NC10 were placed in the dark or under UV irradiation for 3 min. Solutions were scanned using a Cintra 202 spectrometer. The solutions containing 30 µM curcumin and selective concentrations of FeCl2 or FeCl3 were also measured.
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Cell culture and MTT assay
Mouse melanoma B16-F10 cells were obtained from the Culture Collection and Research Center (Hsinchu, Taiwan). Cells were cultured in 25 cm2 tissue culture flasks (Nunc) containing DMEM, 10 % (v/v) FBS, penicillin (100 IU/mL), and streptomycin (100 µg/mL). Flasks were maintained at 37 °C in a humidified incubator under 5 % CO2 and 95 % air. One day before treatment, the cells were harvested from the flasks using PBS containing 0.15 % trypsin and 0.08 % EDTA, and seeded in 96-well plates (1.5 × 104 cells/well in 100 µL of medium). The cytotoxicity of NC10, curcumin, and combinations of NC10 and curcumin were evaluated by the MTT assay. The freshly prepared NC10 and curcumin stock solutions (10 mM in DMSO) were diluted and added to each well. Cells treated with solvent alone were used as controls. After incubation for 24 h or 48 h, the medium in wells was removed and cells were washed twice with PBS. The fresh medium (100 µL) containing 0.5 mg/mL MTT was added to each well and cells were incubated for 4 h. After incubation, DMSO was added to the cells to dissolve the reduced MTT product. The absorbance of the reduced MTT product was measured using a microplate reader (BioTek MQX200) at 570 nm.
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Calculation of synergy
The synergy of cotreatment on the inhibition of cell growth was calculated using the value of cell growth percentage according to a previous study [42]. The observed percent inhibition was calculated by (% control – % the treatment). The expected percent inhibition was calculated by (% control – % NC10 treatment) + (% control – % curcumin treatment). Thus, the synergy of the treatment was given by (observed % inhibition/expected % inhibition). Values of synergy greater than 1.0 were considered to have a synergistic effect.
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Results and Discussion
Without UV irradiation, NC10 caused no DNA cleavage after incubation for 5 min. After UV irradiation, the supercoiled plasmid DNA was cleaved by NC10 and adopted the open-circular formation. At increasing concentrations of NC10, the open-circular plasmid DNA was further cleaved and achieved linear formation. With longer incubation times, such as 3 h, NC10 could cleave plasmid DNA without UV irradiation ([Fig. 2]). These results demonstrate that NC10 releases NO spontaneously or under UV irradiation, and displays DNA cleavage activity in a dose-dependent manner similar to the DNIC and RRE previously synthesized in our laboratory [18], [40].
To examine the effect of curcumin on the DNA cleavage activity of NC10, we performed a DNA cleavage assay using NC10 alone or in combination with selective concentrations of curcumin. [Fig. 3 A] shows that after incubation for 18 h in the dark, curcumin alone remained unable to damage plasmid DNA (lanes 2–7), whereas NC10 alone could cleave plasmid DNA ([Fig. 3 A], lane 8). In combinations of 5 µM NC10 with 1 µM, 2.5 µM, or 5 µM curcumin, plasmid DNA cleavage increased with increasing concentrations of curcumin ([Fig. 3 A], lanes 9–11). However, when the curcumin concentration was higher than 10 µM, the DNA cleavage ability of NC10 was inhibited ([Fig. 3 A], lanes 12–14).
To facilitate DNA cleavage by NC10, reactions were conducted under UV irradiation. After UV exposure for 3 min, the plasmid was slightly damaged in the absence of curcumin or NC10 ([Fig. 3 B], lane 1). In the presence of curcumin alone, the amount of cleaved plasmid DNA was not increased, indicating that curcumin caused no DNA cleavage even after UV exposure ([Fig. 3 B], lanes 2–7). Conversely, in the presence of 5 µM NC10 alone, plasmid DNA was cleaved ([Fig. 3 B], lane 8). Combinations of 5 µM NC10 and 1 µM, 2.5 µM, or 5 µM curcumin caused the damage to plasmid DNA to increase ([Fig. 3 B], lanes 9–11). In the presence of 10 µM curcumin, the amount of cleaved DNA was similar to that in the reaction containing NC10 alone ([Fig. 3 B], lane 8 vs. lane 12). This indicates that the additive DNA cleavage effect of curcumin was reduced. Moreover, in the presence of 20 µM or 40 µM curcumin, the amount of cleaved DNA was less compared with that in the reaction containing NC10 alone ([Fig. 3 B], lane 8 vs. lane 13, or 14). This suggests that the DNA cleavage ability of NC10 was partially inhibited by high concentrations of curcumin.
To cleave plasmid DNA completely, reactions were conducted under UV irradiation for 5 min. Again, curcumin alone did not damage plasmid DNA, although NC10 by itself displayed significant plasmid DNA cleavage activity. Almost all supercoiled forms of plasmid DNA were converted into the open-circular plasmid form by 5 µM NC10 ([Fig. 3 C]). In the presence of 1 µM, 2.5 µM, or 5 µM curcumin, the supercoiled form of plasmid was completely cleaved. However, in the presence of 10 µM curcumin, the open-circular form of DNA remained. Moreover, amounts of open-circular DNA were higher than that of open-circular DNA in the reaction with 5 µM NC10 alone, suggesting that curcumin protected the plasmid DNA from being cleaved by NC10 ([Fig. 3 C], lane 8 vs. 12). This protection was not sufficiently strong to destroy the DNA cleavage activity of NC10 because all supercoiled forms of plasmid were still converted into open-circular DNA by NC10. In the presence of 20 µM or 40 µM curcumin, NC10 regained its plasmid DNA cleavage activity and cleaved open-circular DNA again.
To examine the effect of NC10 concentration on DNA cleavage activity, different concentrations of NC10 were combined with 5 µM or 10 µM curcumin in the plasmid DNA cleavage reactions. Again, NC10 displayed a dose-dependent plasmid DNA cleavage activity ([Fig. 3 D], lanes 2–7). In the presence of 5 µM curcumin, the amount of cleaved plasmid increased compared to that with NC10 alone. However, in the presence of 10 µM curcumin, although the amount of cleaved plasmid also increased, we observed that the amount of linear plasmid in the reaction containing 5 µM NC10 was higher than that in the reaction containing 3 µM or 7 µM NC10. This result confirmed the results discussed above that plasmid DNA treated with the combination of 5 µM NC10 and 10 µM curcumin had less cleaved DNA compared with the amount cleaved by other treatments.
In a previous study, we showed that the NO radical scavenger carboxy-PTIO inhibited the DNA cleavage activity of DNIC and RRE [18], [40]. In the current study, we demonstrated that curcumin inhibited the DNA damage caused by NC10. Curcumin acts as an antioxidant through its β-diketone and phenolic moieties. NO residuals bind to a phenolic moiety of curcumin to form the phenoxyl radical [26], [43], [44]. Therefore, curcumin may act as an NO quencher in the NC10-mediated DNA cleavage reaction. We observed that the DNA protective effect of curcumin changed when reactions were conducted in the dark or under UV irradiation. This might be because, in the dark, NO is slowly released from NC10, allowing curcumin to remove the released NO completely. Under UV irradiation, NO is released fast and completely, plausibly preventing curcumin from removing all NO residuals immediately. Moreover, curcumin is UV sensitive, and is liable to disruption after UV irradiation [45]. Therefore, curcumin would lose its NO scavenging activity after exposure to UV irradiation.
Another question on the protective effect of curcumin is that if curcumin only plays a role as an NO radical scavenger, increasing curcumin concentrations would result in reducing DNA cleavage by NC10. However, we unexpectedly found that less DNA cleavage occurred with a combination of 5 µM NC10 and 10 µM curcumin, or a 1 : 2 ratio of NC10 to curcumin. Therefore, an unidentified mechanism associated with DNA cleavage by a mixture of curcumin and NC10 may exist. We therefore hypothesized that curcumin might interact with NO when it still binds to the iron of NC10, and affect the DNA cleavage by NC10. To prove this hypothesis, we performed IR spectroscopy analysis to detect the absorption of the NO bonds of NC10 in the presence of different concentrations of curcumin. [Fig. 4] shows that the νNO stretching frequencies of NC10 appear at 1759 s/cm and 1784 s/cm. In the presence of curcumin, although shifting of the stretching vibrational band of NO was not observed, the intensities of νNO changed as the curcumin concentration varied. In particular, in the 1 : 2 mixture of NC10 and curcumin, the lowest intensity occurred. This result was insufficient to prove our hypothesis. We are currently co-crystallizing NC10 and curcumin to provide direct evidence of the interaction between curcumin and bound NO of NC10.
It is clear that curcumin destroys NO radicals and protects DNA from being damaged by NC10. However, we also observed enhanced DNA cleavage in the presence of curcumin and NC10 at certain concentrations. How could curcumin increase NC10-mediated DNA cleavage? It has been shown that the β-diketone moiety of curcumin could bind to metal ions such as Cu2+, Fe2+, and Zn2+, and form curcumin-metal complexes. These complexes could damage DNA [46], [47], [48]. Therefore, it is possible that curcumin might interact with the iron of NC10 and cause more DNA damage. To explore this possibility, we performed UV/vis spectroscopy to detect whether curcumin-Fe complexes exist in mixtures of curcumin and NC10. [Fig. 5] shows that curcumin absorbed light at a wavelength of 425 nm, whereas NC10 (15 µM) by itself did not absorb light. After exposure to UV irradiation, the absorbance of curcumin at 380 nm increased and the absorbance at 445 nm decreased. This result corresponded to the absorbance spectrums of the solution containing curcumin and Fe2+ or Fe3+. Based on this observation, we propose that formation of a curcumin-Fe complex occurs in the solution containing curcumin and NC10 after exposure to UV irradiation.
We further investigated the effects of iron on the DNA cleavage mediated by NC10 and curcumin. [Fig. 6] shows that both Fe2+ and Fe3+ could cause DNA cleavage in combination with curcumin alone. Increasing the concentration of iron raised the cleavage of DNA. In the presence of 0.5 µM iron and 5 µM curcumin, all plasmid DNA was cleaved. In addition, the presence of Fe2+ or Fe3+ had no effect on DNA cleavage mediated by NC10. Conversely, plasmid DNA remained in a mixture containing 5 µM NC10 and 5 µM curcumin. This indicates that only small portions of iron were available for association with curcumin, and therefore, the amounts of cleaved DNA caused by curcumin-Fe complexes were limited in the mixtures of curcumin and NC10.
To confirm that curcumin enhances NC10-mediated DNA cleavage through the association with iron released from NC10, we added EDTA to the reaction mixtures to determine whether the elimination of iron would affect DNA cleavage by curcumin and NC10. As shown in [Fig. 7], curcumin enhanced DNA cleavage mediated by 5 µM NC10 at low concentrations (< 3 µM), then lost its ability to enhance DNA cleavage activity at concentrations around 6 µM. It regained its ability to enhance DNA cleavage at concentrations greater than 9 µM. In the presence of 0.05 µM EDTA, the enhanced DNA cleavage activity of curcumin was reduced by a combination of 5 µM NC10 and 1.5 µM curcumin, but not in the remaining reactions. To account for this result, it is possible that 0.05 µM EDTA could not compete with higher concentrations of curcumin for binding with iron, resulting in no blocking effect being observed. Despite this inefficient inhibition by EDTA, the results support the need for curcumin to have iron to enhance DNA cleavage mediated by NC10.
We performed the MTT assay to determine the cytotoxicity of NC10 alone or in combination with curcumin. As shown in [Table 1], NC10 displayed dose-dependent cytotoxicity against mouse melanoma B16-F10 cells. In the presence of 5 µM or 10 µM NC10 alone, the survival rates after 24 h incubation were 87 ± 2 % or 61 ± 2 %, respectively. After a further 24 h of incubation, the survival rates of cells became 123 ± 3 % or 98 ± 3 %, respectively. These results indicate that treatment with lower concentrations of NC10 only had a slight effect on the survival of B16-F10 cells. We obtained similar results when the cells were treated with curcumin. The survival rates of cells receiving 5 µM or 10 µM curcumin were 112 ± 4 % or 75 ± 3 %, respectively, after an incubation of 48 h. Conversely, cells receiving cotreatment with NC10 and curcumin had lower survival rates compared with cells receiving treatment with NC10 or curcumin alone at the same dosage. Furthermore, we found that after an incubation of 48 h, the synergistic effect of 10 µM NC10 combined with 5 µM curcumin was 1.33, indicating a synergistic toxic effect, despite the survival rate of cells receiving this combination treatment being 81 ± 4 %. We also noticed that the smallest value of a synergistic effect (0.44) was observed in the cotreatment of 5 µM NC10 with 10 µM curcumin, indicating that, in this combination, the cytotoxicity effects of both NC10 and curcumin were reduced significantly. This result also correlates with the lower DNA cleavage by the same combination of 5 µM NC10 and 10 µM curcumin.
|
Cell growth (%) |
Observed inhibition (%) |
Expected inhibition (%) |
Synergistic effect |
|
|
Treatment 24 h |
||||
|
Control |
95 ± 4 |
|||
|
5 µM NC |
87 ± 2 |
8 |
||
|
10 µM NC |
61 ± 2 |
36 |
||
|
5 µM Cur |
77 ± 3 |
19 |
||
|
10 µM Cur |
56 ± 3 |
41 |
||
|
5 µM NC + 5 µM Cur |
73 ± 1 |
23 |
27 |
0.85 |
|
5 µM NC + 10 µM Cur |
66 ± 4 |
31 |
49 |
0.63 |
|
10 µM NC + 5 µM Cur |
48 ± 5 |
50 |
55 |
0.91 |
|
10 µM NC + 10 µM Cur |
41 ± 3 |
57 |
77 |
0.74 |
|
Treatment 48 h |
||||
|
Control |
119 ± 3 |
|||
|
5 µM NC |
123 ± 3 |
− 3 |
||
|
10 µM NC |
98 ± 3 |
18 |
||
|
5 µM Cur |
112 ± 4 |
6 |
||
|
10 µM Cur |
75 ± 3 |
37 |
||
|
5 µM NC + 5 µM Cur |
115 ± 6 |
3 |
3 |
1 |
|
5 µM NC + 10 µM Cur |
101 ± 4 |
15 |
34 |
0.44 |
|
10 µM NC + 5 µM Cur |
81 ± 4 |
32 |
24 |
1.33 |
|
10 µM NC + 10 µM Cur |
63 ± 2 |
47 |
55 |
0.85 |
Combination treatments using curcumin and organic compounds such as beta-phenylethyl isothiocyanate [49], epigallocatechin gallate [50], gemcitabine [51], and taxol [52] have been shown to be synergistically cytotoxic to cancer cells. In our previous study, we found no synergistic cytotoxicity with the cotreatment of NC03 and curcumin, whereas pretreatment of curcumin followed by treatment with NC03 displayed a synergistic toxic effect against the cancer cells [40]. In the current study, we demonstrated that cotreatment of curcumin with NC10 exerted synergistic cytotoxicity. Moreover, we also uncovered the interplay between NC10 and curcumin in DNA cleavage. Based on our results, we propose a model of NC10 and curcumin-mediated DNA cleavage. In the absence of curcumin, increasing NC10 releases more NO, leading to increased DNA cleavage. In the presence of curcumin, NO residuals are destroyed and the amount of cleaved DNA is reduced. Conversely, curcumin associated with the iron of NC10 results in increased DNA cleavage. Therefore, at increasing curcumin concentrations, NO is completely destroyed and no DNA cleavage is observed. More curcumin-Fe complexes form and cause more DNA damage. Overall, the net picture of DNA cleavage depends on the concentration of curcumin and the concentrations of NO and iron released from NC10.
In conclusion, the results of this study demonstrate that curcumin plays two opposing roles in NC10-mediated DNA cleavage in vitro. Curcumin acts as an NO scavenger and protects DNA from being damaged by NC10. Conversely, curcumin also binds to the iron of NC10, causing DNA cleavage. By manipulating the concentrations of curcumin and NC10, outcomes could entail either DNA protection or DNA cleavage. Finally, under UV irradiation, a combination of NC10 and curcumin (1 : 2 molarity ratio) caused less DNA damage. This unusual result suggests that an unknown interaction between curcumin and NC10 might affect the DNA cleavage activities of the two chemicals.
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Acknowledgements
The authors thank J. K. Yeh and Y. L. Ho for their assistance in this experiment. This work was funded by the National Science Council, Taiwan (NSC 1002321B018001).
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Conflict of Interest
The authors declare that there are no conflicts of interest.
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- 40 Wen YD, Ho YL, Shiau RJ, Yeh JK, Wu JU, Wang WL, Chiou SJ. Synergistic antitumor effect of curcumin and dinitrosyl iron complexes for against melanoma cells. J Organomet Chem 2010; 695: 352-359
- 41 Lee HM, Chiou SJ. trans-Bis(µ-2-hydroxyethanethiolato-κ2S : S)bis[dinitrosyliron(II)](Fe–Fe). Acta Crystallogr 2009; E65: m1600
- 42 Chuang CH, Hu ML. Synergistic DNA damage and lipid peroxidation in cultured human white blood cells exposed to 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone and ultraviolet A. Environ Mol Mutagen 2006; 47: 73-81
- 43 Ahsan H, Parveen N, Khan NU, Hadi SM. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 1999; 121: 161-175
- 44 Barzegar A, Moosavi-Movahedi AA. Intracellular ROS protection efficiency and free radical-scavenging activity of curcumin. PLoS One 2011; 6: e26012
- 45 Tønnesen HH, Karlsen J, van Henegouwen GB. Studies on curcumin and curcuminoids. VIII. Photochemical stability of curcumin. Z Lebensm Unters Forsch 1986; 183: 116-122
- 46 Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimerʼs disease animal models. J Alzheimers Dis 2004; 6: 367-377
- 47 Sumanont Y, Murakami Y, Tohda M, Vajragupta O, Matsumoto K, Watanabe H. Evaluation of the nitric oxide radical scavenging activity of manganese complexes of curcumin and its derivative. Biol Pharm Bull 2004; 27: 170-173
- 48 Perron NR, Brumaghim JL. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell Biochem Biophys 2009; 53: 75-100
- 49 Khor TO, Keum YS, Lin W, Kim JH, Hu R, Shen G, Xu C, Gopalakrishnan A, Reddy B, Zheng X, Conney AH, Kong AN. Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res 2006; 66: 613-621
- 50 Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo . Int J Cancer 2008; 122: 1966-1971
- 51 Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 2007; 67: 3853-3861
- 52 Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem 2005; 280: 6301-6308
Correspondence
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- 47 Sumanont Y, Murakami Y, Tohda M, Vajragupta O, Matsumoto K, Watanabe H. Evaluation of the nitric oxide radical scavenging activity of manganese complexes of curcumin and its derivative. Biol Pharm Bull 2004; 27: 170-173
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- 49 Khor TO, Keum YS, Lin W, Kim JH, Hu R, Shen G, Xu C, Gopalakrishnan A, Reddy B, Zheng X, Conney AH, Kong AN. Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res 2006; 66: 613-621
- 50 Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo . Int J Cancer 2008; 122: 1966-1971
- 51 Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 2007; 67: 3853-3861
- 52 Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem 2005; 280: 6301-6308