Background: In search of a suitable GSH-depleting agent, a novel copper complex viz., copper N-(2-hydroxyacetophenone) glycinate (CuNG) has been synthesized, which was initially found to be a potential resistance modifying agent and later found to be an immunomodulator in mice model in different doses. The objective of the present work was to decipher the effect of CuNG on reactive oxygen species (ROS) generation and antioxidant enzymes in normal and doxorubicin-resistant Ehrlich ascites carcinoma (EAC/ Dox)-bearing Swiss albino mice.
Purpose: 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. 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)b earing 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-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 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-g 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-g and/or tumor necrosis factor-a, from splenic mononuclear cells or patient peripheral blood mononuclear cells and reduce the number of Tregulatory 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.
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