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

Mookerjee, Ananda and Mookerjee Basu, Jayati and Dutta, Pranabananda and Majumder, Surajit and Bhattacharyya, Sankar and Biswas, Jaydip and Pal, Smarajit and Mukherjee, Pratima and Raha, Sanghamitra and Baral, Rathindra N and Das, Tania and Efferth, Thomas and Sa, Gouri Shankar and Ray, Shyamal and Choudhuri, Soumitra K (2006) Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate throughHost-Protective Cytokine-MediatedApoptosis. Clin Cancer Res, 12 (14). pp. 4339-4349.

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    Abstract

    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.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/436
    Subjects: Cancer Biology and Inflammatory Disorder Division
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Mr Shyamal Nath
    Date Deposited: 01 Nov 2011 17:36
    Last Modified: 05 Mar 2013 12:10
    Official URL: htpp://dx.doi.org/10.1158/1078-0432.CCR-06-0001
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