Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate throughHost-Protective Cytokine-MediatedApoptosis

Previously, we have synthesized and characterized a novel Cu(II) complex, copper N-(2-hydroxy acetophenone) glycinate (CuNG).Herein,wehave determined the efficacyofCuNG in overcomingmultidrug-resistant cancer using drug-resistantmurine and human cancer cell lines. Experimental Design: 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 cellcy cle analysis, confocal microscopy, Annexin V binding, and terminald eoxynucleotidyl transferase ^mediated dUTP nick end labeling assay ex vivo. IFN-g and tumor necrosis factor-a 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-g and changes in number of Tregulatory 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-g and its involvement in induction of apoptosis of doxorubicin-resistant CEM/ADR5000 cells. Results: CuNGtreatment could resolve drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-g and/or tumor necrosis factor-a, from splenic mononuclear cells or patient peripheral bloodmononuclear cells and reduce the number ofTregulatory marker-bearing cells while increase infiltration of IFN-g-producingTcells in the ascetic tumor site. Conclusion: Our results show the potential usefulness of CuNG in immunotherapy of drugresistant cancers irrespective of multidrug resistance phenotype