title: Iron N-(2-hydroxy acetophenone) glycinate (FeNG), a non-toxic glutathione depletor circumvents doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo.
abstract: Multidrug resistance-associated protein 1 (MRP1) reduces intracellular anticancer drug accumulation either by co transporting them with glutathione (GSH) or extruding drug-GSH conjugates outside of the cell. Thus, MRP1 confers multidrug resistance (MDR) and worsen successful chemotherapeutic treatment against cancer. Although the exact mechanism of MRP1 involved in MDR remains unknown, the elevated level of intracellular GSH is considered as a key factor responsible for MDR in cancer. Hence the quest for non-toxic molecules that are able to deplete intracellular GSH has profound importance to subdue MDR. The present preclinical study depicts the resistance reversal potentiality of an iron complex; viz. Ferrous N-(2-hydroxy acetophenone) glycinate (FeNG) developed by us in doxorubicin resistant Ehrlich ascites carcinoma (EAC/Dox) cells. FeNG potentiate cytotoxic effect of doxorubicin on EAC/Dox cells ex vivo and also increases the survivability EAC/Dox bearing Swiss albino mice in vivo as well. Moreover, in vivo administration of FeNG significantly depletes intracellular GSH with ensuant increase in doxorubicin concentration in EAC/Dox cells without alternation of MRP1 expression. In addition, intra-peritoneal (i.p.) application of FeNG in normal or EAC/Dox bearing mice does not cause any systemic toxicity in preliminary trials in mouse Ehrlich ascites carcinoma model. Therefore, the present report provides evidence that FeNG may be a promising new resistance modifying agent against drug resistant cancers.
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta, 700 026, India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Ganguly
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakraborty
authors.forename: Kaushik
authors.initials: K
authors.lastname: Banerjee
authors.forename: Shilpak
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Soumya
authors.initials: S
authors.lastname: Basu
authors.forename: Avijit
authors.initials: A
authors.lastname: Sarkar
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Soumitra Kumar
authors.initials: SK
authors.lastname: Choudhuri
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D004317:Doxorubicin / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007501:Iron; D051379:Mice; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005978:Glutathione; D007501:Iron; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C038699:acetophenone; C421109:multidrug resistance-associated protein 1