Dalton Transactions Dynamic Article Links Cite this: Dalton Trans., 2011, 40, 10873 www.rsc.org/dalton PAPER An in vitro and in vivo study of a novel zinc complex, zinc N -(2-hydroxyacetophenone)glycinate to overcome multidrug resistance in cancer Ruma Dey Ghosh, a Satyajit Das, a Avishek Ganguly, a Kaushik Banerjee, a Paramita Chakraborty, a Avijit Sarkar, b Mitali Chatterjee, b Ashis Nanda, c Kiran Pradhan c and Soumitra K. Choudhuri* a Received 24th March 2011, Accepted 19th May 2011 DOI: 10.1039/c1dt10501a Multiple drug resistance (MDR) remains a major clinical challenge for cancer treatment. P-glycoprotein is the major contributor and they exceed their role in the chemotherapy resistance of most of the malignancies. Attempts in several preclinical and clinical studies to reverse the MDR phenomenon by using MDR modulators have not yet generated promising results. In the present study, a co-ordination complex of zinc viz., Zn N-(2-hydroxyacetophenone)glycinate (ZnNG) has been synthesized, characterized and its antitumour activity was tested in vitro against drug sensitive and resistant human T-lymphoblastic leukemic cell lines (CCRF/CEM and CEM/ADR5000 respectively) and in vivo against Ehrlich ascites carcinoma (EAC) implanted in female Swiss albino mice. To evaluate the cytotoxic potential of ZnNG, we used sensitive CCRF/CEM and drug resistant CEM/ADR 5000 cell lines in vitro. Moreover, ZnNG also has the potential ability to reverse the multidrug resistance phenotype in drug resistant CEM/ADR 5000 cell line and induces apoptosis in combination with vinblastine. ZnNG remarkably increases the life span of Swiss albino mice bearing sensitive and doxorubicin resistant subline of EAC in presence and in absence of doxorubicin. In addition, intraperitoneal application of ZnNG in mice does not show any systemic toxicity in preliminary trials in normal mice. To conclude, a novel metal chelate of zinc viz., ZnNG, may be a promising therapeutic agent against sensitive as well as drug resistant cancers. Introduction Zinc, the second most prominent trace metal in the human body after iron, is essential for growth and development and plays an important role in various biological systems. 1 Zinc participates in a number of metabolic functions 2 and its deficiency is associated with increased risk of cancer. 3 More than two thousand transcription factors require zinc for maintenance of their structural integrity and binding to DNA. 4 Zinc deficiency causes growth retardation, immune dysfunction and cognitive impairment. 5,6 Zinc supplementation cures many of these diseases, modulates oxidative stress, improves immune function and pre- vents cancer. 7–10 Metallopharmaceuticals play a significant role in therapeutic and diagnostic medicine. The discovery and development of some new metallodrugs reveal an ever-growing area of research a Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chit- taranjan National Cancer Institute, 37, S.P. Mukherjee Road, 700 026, Kolkata, India. E-mail: soumitra01@yahoo.com; Fax: 91-33-2475-7606; Tel: 91-33-2476-5101/02/04, ext. 332 b Department of Pharmacology, Institute of Post Graduate Medical Educa- tion and Research, Kolkata, India c Department of Chemistry, University of North Bengal, Darjeeling, India in medicinal chemistry. 11 Coordination of organic compounds with metal (chelation) causes drastic changes in the biologi- cal property of both the organic ligand and also the metal moiety. 3 The transition metal complexes of Schiffs’ bases had been designed and synthesized to explore their pharmacological and antitumour activity. 12–15 Previously we had synthesized and characterized Schiffs’ base complexes of copper, iron and cobalt viz., copper N-(2-hydroxyacetophenone)glycinate CuNG, 12,13 iron N-(2-hydroxyacetophenone)glycinate (FeNG) 14 and cobalt N-(2- hydroxyacetophenone)glycinate (CoNG) 15 respectively and found that all these complexes have anticancer activity in drug resistant cancer in vitro and also in vivo. Innumerable anticancer drugs so far have been developed but successful treatment of cancer still remains elusive. The major reasons of failure of chemotherapetic drugs lie with their non-selectivity to cellular targets and the occurrence of the phenomenon of drug resistance. 16 Therefore, for the development of effective anticancer agents, their role in both drug sensitive and resistant cancer cases needs to be evaluated. So in the present work a novel zinc complex, zinc N-(2-hydroxyacetophenone)- glycinate (ZnNG) has been synthesized by coordination with the non-toxic ligand, potassium N-(2-hydroxyacetophenone)glycinate (PHAG) 16 and we studied the effect of ZnNG on cancer cells in This journal is © The Royal Society of Chemistry 2011 Dalton Trans., 2011, 40, 10873–10884 | 10873 Downloaded by Bose Institute on 02 January 2012 Published on 30 June 2011 on http://pubs.rsc.org | doi:10.1039/C1DT10501A View Online / Journal Homepage / Table of Contents for this issue