Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis.
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.
Mookerjee
Ananda
A
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, India.
Mookerjee Basu
Jayati
J
Dutta
Pranabananda
P
Majumder
Surajit
S
Bhattacharyya
Sankar
S
Biswas
Jaydip
J
Pal
Smarajit
S
Mukherjee
Pratima
P
Raha
Sanghamitra
S
Baral
Rathindra N
RN
Das
Tania
T
Efferth
Thomas
T
Sa
Gourisankar
G
Roy
Shyamal
S
Choudhuri
Soumitra K
SK
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
D000970:Antineoplastic Agents; D002614:Chelating Agents; D016207:Cytokines; D003300:Copper; D004317:Doxorubicin