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Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate

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 impor...

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Autores principales: Ganguly, Avishek, Basu, Soumya, Chakraborty, Paramita, Chatterjee, Shilpak, Sarkar, Avijit, Chatterjee, Mitali, Choudhuri, Soumitra Kumar
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889820/
https://www.ncbi.nlm.nih.gov/pubmed/20582168
http://dx.doi.org/10.1371/journal.pone.0011253
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author Ganguly, Avishek
Basu, Soumya
Chakraborty, Paramita
Chatterjee, Shilpak
Sarkar, Avijit
Chatterjee, Mitali
Choudhuri, Soumitra Kumar
author_facet Ganguly, Avishek
Basu, Soumya
Chakraborty, Paramita
Chatterjee, Shilpak
Sarkar, Avijit
Chatterjee, Mitali
Choudhuri, Soumitra Kumar
author_sort Ganguly, Avishek
collection PubMed
description 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 antioxidant N-acetyle-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR. CONCLUSION/SIGNIFICANCE: Our study provides evidence that FeNG, a redox active metal chelate may be a promising new therapeutic agent against drug resistance cancers.
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spelling pubmed-28898202010-06-25 Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate Ganguly, Avishek Basu, Soumya Chakraborty, Paramita Chatterjee, Shilpak Sarkar, Avijit Chatterjee, Mitali Choudhuri, Soumitra Kumar PLoS One Research Article 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 antioxidant N-acetyle-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR. CONCLUSION/SIGNIFICANCE: Our study provides evidence that FeNG, a redox active metal chelate may be a promising new therapeutic agent against drug resistance cancers. Public Library of Science 2010-06-22 /pmc/articles/PMC2889820/ /pubmed/20582168 http://dx.doi.org/10.1371/journal.pone.0011253 Text en Ganguly et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ganguly, Avishek
Basu, Soumya
Chakraborty, Paramita
Chatterjee, Shilpak
Sarkar, Avijit
Chatterjee, Mitali
Choudhuri, Soumitra Kumar
Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title_full Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title_fullStr Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title_full_unstemmed Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title_short Targeting Mitochondrial Cell Death Pathway to Overcome Drug Resistance with a Newly Developed Iron Chelate
title_sort targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889820/
https://www.ncbi.nlm.nih.gov/pubmed/20582168
http://dx.doi.org/10.1371/journal.pone.0011253
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