title: 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 β-diketone, curcumin also exists as a keto-enol tautomer that chelates transition metal ions with high affinity.
  
  
  OBJECTIVE
  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.
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China . Electronic address: zhangweihope@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Changmai
authors.initials: C
authors.lastname: Chen
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Hengfei
authors.initials: H
authors.lastname: Shi
authors.affiliation: School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
authors.forename: Manyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China . Electronic address: erguang@nju.edu.cn.
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002570:Ceruloplasmin / Q000737:chemistry; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D000079923:Copper Transporter 1; D003474:Curcumin / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D009570:Nitriles; D034741:RNA, Small Interfering; C490079:SLC31A1 protein, human; C113580:U 0126; D003300:Copper; D002570:Ceruloplasmin; D003474:Curcumin
keywords: Antitumor; Copper chelation; Curcumin; MAPK