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Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate through Host-Protective Cytokine-Mediated Apoptosis

Authors' Affiliations: Departments of ¹ Environmental Carcinogenesis and Toxicology, ² Surgical Oncology and Medical Oncology, Hospital Unit, ³ Clinical Biochemistry, Hospital Unit, ⁴ In vitro Carcinogenesis and Cellular Chemotherapy, and ⁵ Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute; ⁶ Department of Immunology, Indian Institute of Chemical Biology; ⁷ Department of Animal Physiology, Bose Institute; ⁸ Department of Crystallography and Molecular Biology, Saha Institute of Nuclear Physics, Calcutta, India and ⁹ German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Soumitra K. Choudhuri, Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700 026, India. Phone: 91-33-2476-5101/02/04, ext. 317; Fax: 91-33-2475-7606; E-mail: soumitra01{at}vsnl.net.

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)–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- and tumor necrosis factor- 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- 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- 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- and/or tumor necrosis factor-, 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--producing T cells in the ascetic tumor site.

Conclusion: Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers irrespective of multidrug resistance phenotype.

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