title: Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis.
abstract: OBJECTIVE
  Previously, we have synthesized and characterized a novel Cu(II) complex, copper N-(2-hydroxy acetophenone) glycinate (CuNG). Herein, we have determined the efficacy of CuNG in overcoming multidrug-resistant cancer using drug-resistant murine and human cancer cell lines.
  
  
  METHODS
  Action of CuNG following single i.m. administration (5 mg/kg body weight) was tested in vivo on doxorubicin-resistant Ehrlich ascites carcinoma (EAC/Dox)-bearing mice and doxorubicin-resistant sarcoma 180-bearing mice. Tumor size, ascitic load, and survival rates were monitored at regular intervals. Apoptosis of cancer cells was determined by cell cycle analysis, confocal microscopy, Annexin V binding, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay ex vivo. IFN-gamma and tumor necrosis factor-alpha were assayed in the culture supernatants of in vivo and in vitro CuNG-treated splenic mononuclear cells from EAC/Dox-bearing mice and their apoptogenic effect was determined. Source of IFN-gamma and changes in number of T regulatory marker-bearing cells in the tumor site following CuNG treatment were investigated by flow cytometry. Supernatants of in vitro CuNG-treated cultures of peripheral blood mononuclear cells from different drug-insensitive cancer patients were tested for presence of the apoptogenic cytokine IFN-gamma and its involvement in induction of apoptosis of doxorubicin-resistant CEM/ADR5000 cells.
  
  
  RESULTS
  CuNG treatment could resolve drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-gamma and/or tumor necrosis factor-alpha, from splenic mononuclear cells or patient peripheral blood mononuclear cells and reduce the number of T regulatory marker-bearing cells while increase infiltration of IFN-gamma-producing T cells in the ascetic tumor site.
  
  
  CONCLUSIONS
  Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers irrespective of multidrug resistance phenotype.
authors.affiliation: Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, India.
authors.forename: Ananda
authors.initials: A
authors.lastname: Mookerjee
authors.forename: Jayati
authors.initials: J
authors.lastname: Mookerjee Basu
authors.forename: Pranabananda
authors.initials: P
authors.lastname: Dutta
authors.forename: Surajit
authors.initials: S
authors.lastname: Majumder
authors.forename: Sankar
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.forename: Smarajit
authors.initials: S
authors.lastname: Pal
authors.forename: Pratima
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Raha
authors.forename: Rathindra N
authors.initials: RN
authors.lastname: Baral
authors.forename: Tania
authors.initials: T
authors.lastname: Das
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.forename: Gourisankar
authors.initials: G
authors.lastname: Sa
authors.forename: Shyamal
authors.initials: S
authors.lastname: Roy
authors.forename: Soumitra K
authors.initials: SK
authors.lastname: Choudhuri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D013154:Spleen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D016207:Cytokines; D003300:Copper; D004317:Doxorubicin