targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate针对线粒体细胞死亡途径克服耐药性新开发的铁螯合物.pdf

Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate 1 1 1 1 2 Avishek Ganguly , Soumya Basu , Paramita Chakraborty , Shilpak Chatterjee , Avijit Sarkar , 2 1 Mitali Chatterjee , Soumitra Kumar Choudhuri * 1 Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India, 2 Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India Abstract Background: Multi drug resistance (MDR) or cross-resistance to multiple classes of chemotherapeutic agents is a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are an important determinant of MDR. Therefore, there is an urgent need for development of novel compounds that are not substrates of P-glycoprotein and are effective against drug-resistant cancer. Methodology/Principal Findings: In this present study, we have synthesized a novel, redox active Fe (II) complex (chelate), iron N- (2-hydroxy acetophenone) glycinate (FeNG). The structure of the complex has been determined by spectroscopic means. To evaluate the cytotoxic effect of FeNG we used doxorubicin resistant and/or sensitive T lymphoblastic leukemia cells and show that FeNG kills both the cell types irrespective of their MDR phenotype. Moreover, FeNG induces apoptosis in doxorubicin resistance T lymphoblastic leukemia cell through mitochondrial pathway via generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxi