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Study of the mechanism of action of novel resistance modifying agents overcoming multidrug resistance in cancer.

In search of a suitable resistance modifying agent (RMA) capable of deactivating resistance causing protein (P-gp, MRP) and glutathione (GSH), a number of novel Schiffs bases and their metal chelates were synthesized and characterized. Copper (II) N-(2-hydroxyacetophenone) glycinate (CuNG) was observed to be the most potent in overcoming multi drug resistance (MDR). CuNG increased ROS generation and reduced MRP1 expression in drug resistant EAC/Dox cells while only temporarily depleted GSH. CuNG also modulated the activities of super oxide dismutase, catalase and glutathione peroxidase in different organs of mice bearing MDR-cells like EAC/Dox, sarcoma 180 and Lewis lung carcinoma and thereby reduced oxidative stress.

It was observed that the level of copper in the serum was significantly higher in MDR-cancer bearing animals and also in cancer-patients unresponsive to drugs. The level of serum copper might be considered a biomarker for treatment response. Intramuscular (i.m.) administration of CuNG (5 mg/kg body weight) completely resolved drug resistance in doxorubicin-resistant Ehrlich ascites carcinoma (EAC/Dox) bearing mice and doxorubicin-resistant sarcoma 180 bearing mice. CuNG-treatment resolved drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-[gamma] and/or tumour necrosis factor-[alpha] from splenic mononuclear cells or patient peripheral blood mononuclear cells (PBMC) and reduced the number of T-regulatory marker-bearing cells while increased infiltration of IFN-[gamma]-producing T-cells in the ascitic tumour site. The potential usefulness of CuNG was proved in immunotherapy of drug resistant cancers irrespective of multidrug resistance phenotype.

CuNG treatment modulated the status of tumour-associated macrophages (TAMs) from immunosuppressive to activated nature. The activated TAMs produced high levels of IL-12 along with low levels of IL-10 that not only allowed strong Th1 response marked by generation of high levels of IFN-[gamma] but also reduced activation induced T-cell death. CuNG treatment of PBMC from chemo and/or radiotherapy refractory cancer patients also modulated their cytokine status. Most intriguingly, CuNG-treated TAMs could influence reprogramming of TGF-[beta] producing CD4 [+ or -] CD25 [+ or -] T-cells towards IFN-[gamma] producing T-cells. CuNG was found to be effective in immunotherapy of drug-resistant cancers through reprogramming of TAMs that in turn reprogrammed the T-cells and reeducated the T-helper function to elicit proper anti-tumorogenic Th1 response that effectively reduce tumour growth.

Phospho P38 was elevated following CuNG treatment in vitro which might cause the elevation of IL-12 and change in T-helper response towards Th1. CuNG also down regulated phospho AKT level which remained elevated in TAMs and helps in IL-10 production.

Synthesis and characterization of another RMA, viz., N-(2-methoxyphenyl)-3-methoxysalicylaldimine was also undertaken and X-ray powder structure and anticancer activity of the compound was determined.

The results of the study showed the potential usefulness of CuNG in immunotherapy of drug resistant cancers through programming of TAMs that in turn programme the T cells and reduces the T helper function to elicit proper anti-tumourogenic Th1 response that effectively reduce tumour growth.

The modulation of the behavior of TAMs by ROS generating metal chelate like CuNG is a significant contribution which may pave the way of developing new drugs for the treatment of cancer irrespective of the drug resistance phenotype.

Publications

1. Mookerjee, A., Mookerjee, J., Majumder, B.S., Chatterjee, S., Panda, G.S., Dutta, P., Pal, S., Mukerjee, P, Efferth, T., Roy, S. and Choudhuri, S.K. A novel copper complex induces ROS generation in doxorubicin resistant Ehrlich ascites carcinoma cells and increases activity of antioxidant enzymes in vital organs in vivo. BMC Can 6:267, 2006.

2. Mookerjee, A., Basu, J.M., Dutta, P, Majumder, S., Bhattacharyya, S., Baral, R.N., Das, T., Mukherjee, P., Efferth, T., Raha, S., Sa, G., Biswas, J., Pal, S., Roy, S. and Choudhuri, S.K. Overcoming drug resistant cancer by a newly developed copper chelate through host protective cytokine-mediated apoptosis. Clin Can Res 12: 4339, 2006.

3. Choudhuri, S.K., Mookerjee, A., Chatterjee, S. and Biswas, J. A novel approach of overcoming multidrug resistance in cancer through immunomodulation. Int JMolMed20: S5, 2007.

4. Chattopadhyay, B., Basu, S., Chakraborty, P Choudhuri, S.K., Mukherjee, A. and Mukherjee, M. Synthesis, spectroscopic characterization, X-ray powder structure analysis, DFT study and in vitro anticancer activity of N-(2-methoxyphenyl)-3-methoxysalicylaldimine. J Mol Struc 932: 90, 2009.

5. Majumer, S., Chatterjee, S., Pal, S., Biswas, J., Efferth, T. and Choudhuri, S.K. The role of copper in drug-resistant murine and human tumours. Biometals 22:377, 2009.

6. Chatterjee, S., Mookerjee, A., Basu, J.M., Chakraborty, P., Ganguly, A., Adhikary, A., Mukhopadhyay, D., Ganguli, S., Banerjee, R., Ashraf, M., Biswas, J., Das, PK., Mitali Chatterjee, S., Das, T. and Choudhuri, K. Chelate modulates tumour associated macrophages to promote anti-tumor response of T cells. Plos One 4:1, 2009.

Dr. Soumitra Kumar Choudhuri

Department of In-vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata
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Title Annotation:ABSTRACTS: Some Research Projects Completed Recently
Author:Choudhuri, Soumitra Kumar
Publication:ICMR Bulletin
Article Type:Abstract
Geographic Code:9INDI
Date:Feb 1, 2010
Words:792
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