Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis

Mookerjee, Ananda ; Mookerjee Basu, Jayati ; Dutta, Pranabananda ; Majumder, Surajit ; Bhattacharyya, Sankar ; Biswas, Jaydip ; Pal, Smarajit ; Mukherjee, Pratima ; Raha, Sanghamitra ; Baral, Rathindra N. ; Das, Tania ; Efferth, Thomas ; Sa, Gourisankar ; Roy, Shyamal ; Choudhuri, Soumitra K. (2006) Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis Clinical Cancer Research, 12 (14). pp. 4339-4349. ISSN 1078-0432

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Official URL: http://clincancerres.aacrjournals.org/content/12/1...

Related URL: http://dx.doi.org/10.1158/1078-0432.CCR-06-0001

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-γ and tumor necrosis factor-α 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-γ 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-γ 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-γ and/or tumor necrosis factor-α, 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-γ-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.

Item Type:Article
Source:Copyright of this article belongs to American Association for Cancer Research.
ID Code:110482
Deposited On:31 Jan 2018 09:39
Last Modified:31 Jan 2018 09:39

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