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Curcumin is a biologically active copper chelator with antitumor activity.

ABSTRACT

Background: Curcumin is a natural product with antitumor activity. The compound targets multiple cell signaling pathways, including cell survival and proliferation, caspase activation and oncogene expression. As a [beta]-diketone, curcumin also exists as a keto-enol tautomer that chelates transition metal ions with high affinity.

Purpose: Copper has an integral role in promoting tumor growth and angiogenesis. This study aims to investigate whether curcumin exerts its antitumor activity through copper chelation.

Methods: Copper chelation ability of curcumin was validated by measuring US/VIS spectrum. The antitumor activity and in vivo copper removal ability of curcumin was determined in a murine xenograft model. The effect of curcumin on copper-induced MAPK activation and cell proliferation was determined in cell culture system.

Results: Administration of curcumin to tumor-bearing animals resulted in suppression of A549 xenograft growth, an effect that was also observed in animals treated with ammonium tetrathiomolybdate (TM), a metal chelator used for copper storage disorders clinically. The inhibition on tumor growth was associated with reduction of copper concentrations in the serum of treated groups. In cell culture studies, we showed that copper promoted cell proliferation through Erk/MAPK activation. Treatment with curcumin or U0126, a specific MAPK inhibitor, or suppression of cellular uptake of copper by siRNA knockdown of copper transporter protein 1 (CTR1) blocked copper-induced cell proliferation.

Conclusions: This study therefore demonstrates curcumin antitumor effect to its copper chelation capability. These results also implicate copper chelation as a general mechanism for their action of some biologically active polyphenols like flavonoids.

Keywords:

Curcumin

Copper chelation

Antitumor

MAPK

Introduction

Naturally occurring polyphenols have metal ion chelating property. Curcumin, isolated from the rhizomes of Curcuma longa, chelates copper and irons with high affinity (Baum and Ng 2004). The compound has anti-oxidant, anti-inflammatory and antitumor activity (Dhillon et al. 2008; Goel et al. 2008; Surh 2003). It inhibits cell proliferation, invasion, metastasis, and angiogenesis of different cancers targeting multiple cell signaling pathways, including cell survival and proliferation, caspase activation and oncogene expression, and mitochondrial pathways (Goel et al. 2008; Ravindran et al. 2009; Yadav and Aggarwal 2011). One may ask how such a simple molecule like curcumin possesses such diverse activity. Curcumin contains phenolic groups and a [beta]-diketone structural feature. The compound also exists as a keto-enol tautomer in aqueous solution that can form stable complexes stoichiometrically with transition metals including copper (II) (Kanhathaisong et al. 2010).

Copper is an essential trace element for human health (Scheiber et al. 2013b). Copper (1/11) functions as a structural and catalytic cofactor for enzymes that participate in energy generation, cellular metabolism, oxygen transport, signal transduction, and angiogenesis. Once absorbed in the small intestine and stomach, copper in the body normally undergoes enterohepatic circulation. The concentrations of copper in the human body are tightly regulated at the levels of cells, organs, and the body. Eukaryotic cells uptake copper using transporters on the plasma membrane known as CTR proteins such as CTR1 that mediates both copper (Kim et al. 2008) as well as anticancer drug cisplatin uptake (Holzer et al. 2006; Ishida et al. 2010). The majority of copper in the blood stream are associated with copper binding proteins since free copper ions have the potential to initiate production of toxic oxygen radical species. In human plasma, more than 95% of total copper is associated with ceruloplasmin (Cp), copper carrier and a ferroxidase that is also responsible for iron metabolism, while less than 5% of copper ions are associated with other proteins (Heilman and Gitlin 2002).

Copper deficiency is very rare since copper is ubiquitous and daily requirement for copper is low. Abnormal accumulation of copper however has strong association with neurodegenerative disorders, diabetes, and cancer (Kim et al. 2008; Scheiber et al. 2013a). Copper plays an integral role in promoting tumor growth and angiogenesis since it functions as a co-factor for several pro-angiogenic molecules like VEGF (Crowe et al. 2013; Finney et al. 2009). In addition, copper ions also participate in MAPK pathway signaling in promoting cell proliferation and angiogenesis (Brady et al. 2014; Narayanan et al. 2013; Turski et al. 2012). Serum levels of copper and Cp are elevated in cancer patients (Coates et al. 1989; Gupte and Mumper 2009). Therefore, strategies aimed at lowering the levels of bioavailable copper have been tested for new anticancer therapeutics. TM is a copper lowering agent currently used for the treatment of genetic diseases of copper accumulation syndromes and metal poisoning and has demonstrated therapeutic efficacy in patients with a variety of tumors (Brewer 2014; Jain et al. 2013). Other drugs tested as copper chelators include trientine and D-penicillamine (Brem et al. 2005; Brewer 2014; Cooper 2011; Goodman et al. 2005).

Given the importance of copper ions in tumor cell proliferation and growth, we tested whether curcumin exerted its antitumor activity through copper chelation. Using a xenograft model of human lung carcinoma A549 cells, we showed that oral administration of curcumin or TM resulted in reduction of copper in the serum. The reduction correlated with inhibited tumor growth and angiogenesis. In addition, we showed curcumin treatment or CTR1 silencing to limit copper intake inhibited copper-induced Erk/MAPK activation (Narayanan et al. 2013). This study uncovers copper chelation as a potential mechanism of curcumin antitumor activity.

Materials and methods

Reagents

The following chemicals were purchased from Sigma-Aldrich (St. Louis, MO): curcumin (catalog number 08511, analytical standard, for UV/VIS spectroscopic studies and cell culture studies; C1386 for animal studies), Cu[Cl.sup.2] * 2[H.sub.2]O (C3279), ammonium tetrathiomolybdate (323446), ferrozine (160601), Fe[(N[H.sub.4]).sub.2] (S[O.sub.4])2 * 6[H.sub.2]O (203505). Antibodies against JNK (#9252) and p-JNK (#4668S, T183/Y185), p38 (#9212) and p-p38 (#9211S, T180/Y182), and CTR1 (#13086S) were purchased from Cell Signaling Technology (Danvers, MA). Antibodies to Erkl (K-23, sc-94), p-Erkl/2 (T202, sc-101760), and ceruloplasmin (N-20, sc-21240) were from Santa Cruz Biotechnology (Dallas, TX). Antibody against GAPDH (MB001) was from Bioworld Technology (Minneapolis, MN). HRP-conjugated secondary antibodies were purchased from Bio-Rad, and Alexa Fluor-conjugated antibodies were from Life Technologies (Carlsbad, CA). BCA Protein Assay Kit (P0012) was purchased from Beyotime Institute of Biotechnology (Haimen, China). Serum VEGF was measured in triplicate using an ELISA kit (BRK-E80-82850312, Beijing, China).

Cell cultures

Human lung carcinoma A549 cells (ATCC[R] Number: CCL-185[TM]) were purchased from ATCC (Manassas, VA). The cells were cultured in Dulbecco's modified Eagle's medium (DMEM), supplemented with 10% heat inactivated fetal bovine serum (FBS), L-glutamine, nonessential amino acids, sodium pyruvate (Life Technologies) at 37[degrees]C in a humidified atmosphere with 5% C[O.sub.2].

UV/VIS spectroscopic study

We used a reported protocol to investigate copper ion-binding properties of curcumin (Baum and Ng 2004). UV/VIS spectra were recorded on a Shimadzu UV-2550 spectrophotometer at 25[degrees]C. Typical titration experiments were performed by mixing varying amount of Cu[Cl.sub.2] (10 mM stock solution) with 1 ml of 20 [micro]M curcumin. The curcumin solution was freshly prepared each time by dilution of a curcumin stock (10 mM in methanol) into 20 mM phosphate buffer (pH 7.2). A single scan from 200 to 700 nm was conducted within 30-60 s.

Western blotting analysis

Total cell lysates were prepared using a lysis buffer containing 150 mM NaCl, 50 mM Tris-HCl (pH 7.4), 1% NP-40, and a cocktail of protease-inhibitors (Roche). The proteins were separated by SDS-PAGE and transferred to PVDF membrane (Millipore) for immunoblotting analysis. GAPDH was used as a loading control. The images were captured using a ChemiScope imaging system (Shanghai, China).

Flow cytometry study

Flow cytometry analysis was performed on FACS Calibur (BD Biosciences, San Jose, CA) to determine the knockdown effect of CTRL After rinsed with ice-cold PBS, the cells were collected, blocked with 1% dry milk in PBS, and stained with anti-CTRl antibody on ice for 60 min. Cell surface bound antibody was detected by incubation with Alexa Fluor 568-labeled anti-rabbit antibody and analyzed with Flowjo 7.6.1 software (Tree Star, Ashland, OR).

shRNA knockdown

Human CTR1 is encoded by the SLC31A1 gene (NM_001859). The SLC31A1 targeting shRNA or a noncoding control (shNC), cloned in the GV248 vector, was purchased from GeneChem (Shanghai, China). The targeting sequence information is as following:

#1: GTACAGGATACTTCCTCTT (nt 506-524 of coding range);

#2; GTAAGTCACAAGTCAGCAT (nt 284-302 of coding range);

#3: TGCCTATGACCTTCTACTT (nt 128-146 of coding range);

shNC: TTCTCCGAACGTGTCACGT.

To knockdown CTR1 expression, A549 cells in 6-well plates were transfected with a control shRNA or CTR1 targeting shRNA (1.5 [micro]g/well) using lipofectamine 3000 (Life Technologies). The cells were harvested at 48 h post transfection for protein expression analysis by western blotting or in combination with FACS analysis. CTR1 expression was routinely suppressed by more than 50-70% with those conditions, as was determined by western blotting and FACS analyses (Fig. 1A and B). For animal studies, we generated a pool of CTR1 knockdown cells. Briefly, A549 cells were transfected with shRNA #2 targeting CTR1 expression for 48 h. The cells were then treated with puromycin (1.5 [micro]g/ml) for another 48 h. The cells were detached by trypsinization and replated in a culture dish for another 16 h to allow cells to recover. The effect of CTR1 knockdown was verified by flow cytometry prior to implantation in animals.

Animal model

All experimental procedures were carried out strictly in accordance with the guide for the care and use of laboratory animals and the related ethical regulations instilled at Nanjing University Medical School. Athymic nu/nu (BALB/c) mice of 4 weeks of age were purchased from Model Animal Research Center of Nanjing University, and were housed under pathogen-free conditions on a 12/12 h light/dark cycle with free access to food and water.

A549 cells or CTR1 knockdown A549 cells were resuspended in ice-cold serum-free medium (SFM) at 1 x [10.sup.7]/ml. The cells were mixed with equal volume of Matrigel (BD Biosciences) and 1 x [10.sup.6] cells per mouse were implanted subcutaneously (s.c.) in the right flank near the rear leg under ketamine-xylazine anesthesia. When palpable tumors were detected (the average volume of tumors was approximately 0.12 [cm.sub.3]), the animals were randomly grouped (n = 5) and then treated with a vehicle (control group), TM (50 mg/kg), or curcumin (100 mg/kg) every other day by oral gavage for three consecutive weeks. Curcumin solution was freshly prepared by dilution of a DMSO stock into normal saline (final DMSO at approximately 1%). Tumor growth was measured twice weekly using a Vernier calipers (major and minor axis) and the volume of tumors ([cm.sub.3]) were calculated by the following equation: length x square of width then divided by 2.

Atomic absorption spectrometry (AAS)

Blood samples were centrifuged for 10 min at 500 xg to collect serum with a micropipette. The sera were kept in a refrigerator at -70[degrees]C until analysis. For copper measurement, serum samples collected at the beginning (baseline copper level) and the end of the experiment were processed by nitrification with 10% nitric acid at 100[degrees]C for 10 min. Copper content from 3 individual animals was determined at the Analytic Core Facility at Nanjing University using a Hitachi 180-80 atomic absorption spectrometer.

Determination of ceruloplasmin content by ferroxidase activity assay

Serum ceruloplasmin content was determined by immunoblotting assay. The ferroxidase activity was determined by an in-gel activity assay (Chen et al. 2004). Mouse serum was mixed with a Laemmli loading buffer without a reducing reagent. The samples were separated on a 6% Tris-glycine polyacrylamide gel under native conditions. The gel was rinsed and then soaked in a buffer containing 100 mM sodium acetate (pH 5.0) and 0.2 mM Fe[(N[H.sub.4]).sub.2] [(S[O.sub.4]).sub.2] at 37[degrees]C for 2 h. The gel was then washed with sodium acetate buffer and rehydrated with freshly prepared ferrozine solution (15 mM in water). Color development was monitored and photographed.

Immunostaining studies

Tissue samples were fixed with 4% paraformaldehyde, dehydrated in ethanol, and embedded in paraffin. The slides were then deparaffinized. For immunohistochemical staining, the slides were treated with 3% [H.sub.2][O.sub.2], followed by blocking with 10% horse serum in PBS for an hour. The samples were stained with anti-Ki-67, anti-cleaved caspase-3 (1:100 dilution in 0.5% bovine serum albumin in PBS) for 2 h, followed by a biotinylated secondary antibody for another 30 min, and then streptavidin-HRP for 20 min, with PBS washes after each incubation. The slides were developed by incubation with the 3,30-diaminobenzidine (DAB) substrate kit. For immunofluorescence staining, tissue sections were stained with anti-CD31 (1:100) antibody for 2 h, followed by Alexa Fluor 488 conjugated secondary antibody (green) to visualize tumor endothelial cells. Nuclei were stained with DAP1 (blue).

The images from Ki-67, cleaved-Caspase 3 and mouse CD31 staining were collected from five fields per section under 200x magnifications and processed using NIH ImageJ software. Staining intensity was measured from five randomly selected views using Image Pro Plus software (Media Cybernetis, Rockville, MD). Five mice from each group were included for statistical analysis.

Statistical analysis

Data were analyzed with GraphPad Software (San Diego, CA). Statistical significance of differences was assessed with Student's t test for two groups or one-way ANOVA for multiple groups, p < 0.05 values were considered significant. All independent parameters are mean [+ or -] standard error of mean (SEM) of results in at least 3 independent experiments unless otherwise stated.

Results

Curcumin chelates with [Cu.sup.2+] in vitro and suppresses tumor growth in vivo

The [beta]-diketone structural element in curcumin can isomerize into keto-enol form (Fig. 2A) that chelates [Cu.sup.2+] ion in a 2:1 ratio in aqueous solutions (Kanhathaisong et al. 2010). UV/VIS spectrometry was performed to demonstrate that curcumin complexed with copper (II) since the maximum absorption ([[lambda].sub.max]) for curcumin and curcumin-[Cu.sup.2+] was at approximately 430 and 360 nm, respectively (Kanhathaisong et al. 2010; Zhao et al. 2010). As shown in Fig. 2B, the [[lambda].sub.max] for curcumin was determined at approximately 427 nm. Addition of [Cu.sup.2+] resulted in a decline of intensity of the 427 nm peak and the appearance of a new peak at approximately 362 nm, indicating the formation of curcumin-[Cu.sup.2+] complexes.

To determine whether curcumin exerts antitumor activity through copper chelation, athymic nude mice bearing A549 xenograft were treated with normal saline (control), 100 mg/kg of curcumin (oral, every other day), or a control of 50 mg/kg TM (oral, every other day), regimes that have been reported as effective against tumor growth in nude mice (Anand et al. 2008; Pan et al. 2002). For comparison, we also included a group of mice that were implanted with A549 cells that had the CTR1 silencing by shRNA (shCTRl group, without treatment). As shown in Fig. 2C, both curcumin and TM treatment suppressed tumor growth. The average of tumor sizes in curcumin and TM-treated groups were 0.35 [+ or -] 0.19 and 0.25 [+ or -] 0.12 [cm.sub.3], compared to that of 1.38 [+ or -] 0.55 [cm.sub.3] in the untreated control group, representing a reduction of 74.6% and 81.9% in tumor sizes, respectively. In supporting that copper plays a role in tumor growth, suppression of CTR1 expression resulted in significant reduction of tumor growth (0.26 [+ or -] 0.14 [cm.sub.3]).

Curcumin is an effective copper chelator in vivo

Copper levels in the serum were first determined directly by AAS method. A baseline copper level in the serum was determined at 0.61 [+ or -] 0.10 mg/L (approximately 9.6 [+ or -] 1.6 [micro]M) using the sera drawn at the beginning of the experiment from 3 mice. For comparison, the average levels of copper (I/II) in the untreated control, curcumin- or TM-treated groups were determined at 0.71 [+ or -] 0.08, 0.27 [+ or -] 0.15, 0.21 [+ or -] 0.12 mg/L, respectively (Fig. 3A), indicating curcumin treatment significantly lowered serum copper levels. Although significant inhibition of tumor growth was observed in the shCTRl group, copper levels in this group were not significantly reduced (0.64 [+ or -] 0.15 mg/L).

We also assessed the changes of copper levels in the serum by measuring ceruloplasmin indirectly with western blotting and an in-gel ferroxidase activity assay since serum ceruloplasmin is widely used as an indicator of serum copper levels (Heilman and Gitlin 2002). Consistent with AAS result, curcumin or TM treatment reduced Cp levels and ferroxidase activity by approximately 50-60% (Fig. 3B), indicating that curcumin had the ability to remove copper from animals while suppressing xenograft tumor growth.

Suppression of tumor growth and angiogenesis by copper chelation

The inhibitory effect of curcumin on tumor growth was confirmed with reduction of cell proliferation and increases in cell apoptosis. Compared to the untreated control, Ki-67 staining in TM-treated group was significantly reduced. The effect on Ki-67 staining in curcumin-treated or shCTRl group was less obvious, but significant (Fig. 4A). In addition, we also detected increased caspase-3 cleavage in curcumin and TM treated groups (Fig. 4B). Those results indicated that copper removal or inhibition of copper uptake by shRNA treatment suppressed tumor growth.

We also detected reduced production of VEGF, an angiogenesis inducer, in curcumin- and TM-treated groups (Fig. 4C). VEGF in shCTRl group was also reduced but to a less significant degree (from approximately 210 pg/ml to 190 pg/ml), even though tumor growth in this group was significantly inhibited. When examined for CD31, a marker for angiogenesis, it was noticed that tumors from the control group were highly vascularized; whereas, curcumin or TM treatment, or knockdown of CTR1 expression, resulted in marked reduction in CD31 staining (Fig. 4D). Those results indicated that copper chelation suppressed tumor growth and angiogenesis.

Curcumin inhibits [Cu.sup.2+]-induced Erk/MAPK activation and cell proliferation

Copper promotes tumor growth by activation of protein kinases regulating cell proliferation as well as by promoting angiogenesis (Finney et al. 2009; Lowndes and Harris 2005). We first investigated MAPK activation by treating A549 cells with varying amount of Cu[Cl.sub.2]. As shown in Fig. 5A, copper treatment of A549 cells dose-dependently activated Erk/MAPK, while no obvious effect on JNK and p38 activation was detected in those samples. The effect was copper specific since suppression of CTR1 expression significantly reduced [Cu.sup.2+]-induced Erk phosphorylation (Fig. 5B).

We next investigated whether copper had the ability to promote A549 cell proliferation. To this end, A549 cells remained untreated or were treated with varying amount Cu[Cl.sub.2]. To minimize the effect of serum on cell growth, the cells were maintained in 2% FBS during copper treatment. The cells were harvested at 24 h after treatment and cell numbers were enumerated. A549 cells proliferated by 43% in the untreated control. Treatment with 5,10 or 15 [micro]M [Cu.sup.2+] resulted in increased cell proliferation by 103,144, and 169%, respectively (Fig. 5C). Consistent with its role in promoting cell proliferation, Erk inhibition with U0126 significantly blocked [Cu.sup.2+]-induced cell proliferation (Fig. 5D).

We also investigated whether chelation of copper by curcumin would affect copper-induced Erk activation. We first determined a non-inhibitory concentration of curcumin against A549 cell growth by obtaining an GI5o (growth inhibition of 50%) value of approximately 20.7 [micro]M within 48 h. A549 cells were therefore treated with 0.3-10 [micro]M curcumin prior to addition of copper to induce Erk/MAPK activation. As shown in Fig. 5E, treatment of A549 cells with 3 and 10 [micro]M curcumin significantly reduced Erk phosphorylation by [Cu.sup.2+]. We also tested whether curcumin had the ability to block copper-induced cell proliferation. As shown in Fig. 5F, unstimulated A549 cells proliferated by approximately 48% in a medium containing 2% FBS 24 h after plated. For comparison, the cells proliferated by approximately 114% in the medium containing 5 [micro]M Cu[Cl.sub.2]. Curcumin at 10 [micro]M did not significantly inhibit A549 cell growth, curcumin at 3 and 10 [micro]M however reduced copper-induced A549 growth down to 78 and 50%, respectively. Those results therefore link curcumin copper lowering ability to its anti-proliferation activity.

Discussion

Curcumin is a major ingredient isolated from turmeric roots, a herb medicine that has been used in Chinese and Indian medicine for thousands of years with demonstrated therapeutic efficacies. Curcumin preparations or turmeric powders, generally recognized as safe (GRAS) as a food additive by the FDA, are currently under clinical trials for antitumor and anti-ageing effect. We showed here that administration of curcumin resulted in reduction of copper in the serum. The effect on copper depletion was as effective as TM, a clinically used copper lowering agent that is currently tested for melanoma therapy (Brady et al. 2014). Depletion of copper or knockdown of CTR1 correlated with retarded growth of tumor xenograft as well as inhibition of signaling events for cell proliferation, indicating curcumin exerts antitumor effect through copper chelation.

Many studies have shown copper to be an obligatory cofactor in the process of tumor growth and angiogenesis (Finney et al. 2009; Lowndes and Harris 2005). Growth factors in angiogenesis require binding to copper in order to function properly (D'Andrea et al. 2010). Copper also binds directly to MEK1 and regulates downstream Erk/MAPK activation of cell growth (Turski et al. 2012). Curcumin inhibits several enzymes like lipoxygenase 1, nitric oxide synthase of proinflammatory response either directly or indirectly. Some of the enzymes are metalloproteins, of which curcumin may affect directly by metal chelation. Its metal chelation capability of curcumin thus could be a common denominator for curcumin biological activities since lowering copper availability with TM produces similar scope of activities through inhibition of copper dependent signaling and cytokine production (Brewer 2014). We provided strong evidence demonstrating that curcumin displays its antitumor effect by copper chelation: by direct detection of copper with AAS and by detection of copper binding protein, by gene knockdown study and by investigation of signaling events. Those studies establish curcumin suppresses tumor cell proliferation and tumor growth through copper chelation.

It is worthy of noting that the bioavailability of curcumin is relatively low, even though some promising effect have been documented from clinical trials and human studies (Sharma et al. 2005; Shen and Ji 2012). In a pharmacodynamics and pharmacokinetic study, no curcumin nor its metabolites was detected in the plasma or urine of patients who had been given curcuma extract at doses up to 2.2 g/day for up to 29 days (Sharma et al. 2001). A Phase II trial of patients with advanced pancreatic cancer reported curcumin in the plasma at approximately 100 nM (Dhillon et al. 2008), concentrations that are far below those demonstrated in in vitro studies. Curcumin is metabolized by glucuronidation and sulfation and is excreted from the urine and feces (Vitaglione et al. 2012). In addition, curcumin undergoes rapid degradation in aqueous solution (Griesser et al. 2011; Wang et al. 1997), raising the question whether other factors are responsible for curcumin activities (Shen and Ji 2012). Our data suggest that curcumin may simply exert its effect indirectly through metal ion chelation.

Metal chelation has been tested as a therapeutic alternative for cancers. The demonstration of curcumin to effectively lower serum copper and copper binding protein levels may also have significant implication in chronical diseases since elevated copper has been detected in people with obesity and neurodegenerative diseases (Scheiber et al. 2013a; Sun et al. 2012).

ARTICLE INFO

Article history:

Received 25 August 2015

Revised 12 November 2015

Accepted 19 November 2015

Conclusions

Our results establish a strong link of curcumin antitumor activity to its copper chelation capability since administration of curcumin resulted in reduced serum levels of copper and copper-binding protein ceruloplasmin. Curcumin inhibits tumor cell proliferation by inhibition of MAPK activation. The results may also help to explain why a compound as simple as curcumin may simply exert their activities through a common denominator like a metal ion described here.

Conflict of interest

The authors declare there are no conflicts of interest.

Disclosure statement

The authors have nothing to disclose.

Acknowledgments

WZ and MY were supported by a grant from the Scientific Research Foundation of Graduate School of Nanjing University. We thank Zhu van Latz to proof-read this manuscript. This work was partially supported by grants from National Natural Science Foundation of China (NSFC 81121062, 81371772).

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Wei Zhang (a,b), **, Changmai Chena (a,c), Hengfei Shi (a,b), Manyi Yang (d), Yu Liu (b,1), Ping Ji (a,b), Huijun Chen (b), Ren Xiang Tan (a,c), Erguang Li (a,b), *

(a) Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

(b) Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China

(c) College of Life Sciences, Nanjing University, Nanjing, China

(d) School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

Abbreviations: AAS, atomic absorption spectrometry; Cp, ceruloplasmin; CTRL copper transporter 1; Erk, extracellular matrix regulated kinase; MAPK, mitogen-activated protein kinase; shRNA, small-hairpin RNA; TM, tetrathiomolybdate.

* Corresponding author. Tel.: +862583593193.

E-mail addresses: zhangweihope@163.com (W. Zhang), erguang@nju.edu.cn (E. Li).

** Corresponding author. Medical School, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Tel.: +86 25 83593193; fax: +86 25 83686451.

(1) Current address: College of Arts and Sciences, University of San Francisco, CA, USA.

http://doi.org/10.1016/j.phymed.2015.11.005
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Author:Zhang, Wei; Chena, Changmai; Shi, Hengfei; Yang, Manyi; Liu, Yu; Ji, Ping; Chen, Huijun; Tan, Ren Xi
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9CHIN
Date:Jan 15, 2016
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