Abstract | 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-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. CONCLUSION: Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers irrespective of multidrug resistance phenotype.
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Authors | Ananda Mookerjee, Jayati Mookerjee Basu, Pranabananda Dutta, Surajit Majumder, Sankar Bhattacharyya, Jaydip Biswas, Smarajit Pal, Pratima Mukherjee, Sanghamitra Raha, Rathindra N Baral, Tania Das, Thomas Efferth, Gourisankar Sa, Shyamal Roy, Soumitra K Choudhuri |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 12
Issue 14 Pt 1
Pg. 4339-49
(Jul 15 2006)
ISSN: 1078-0432 [Print] United States |
PMID | 16857809
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Chelating Agents
- Cytokines
- Copper
- Doxorubicin
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
- Carcinoma, Ehrlich Tumor
(drug therapy)
- Cell Line, Tumor
- Cell Proliferation
- Chelating Agents
(pharmacology)
- Copper
(chemistry)
- Cytokines
(metabolism)
- Doxorubicin
(pharmacology)
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Humans
- Leukocytes, Mononuclear
(metabolism)
- Lymph Nodes
(pathology)
- Mice
- Neoplasm Transplantation
- Neoplasms
(drug therapy)
- Spleen
(metabolism)
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