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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2889820?pdf=render |
| _version_ | 1818991128511250432 |
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| author | Avishek Ganguly Soumya Basu Paramita Chakraborty Shilpak Chatterjee Avijit Sarkar Mitali Chatterjee Soumitra Kumar Choudhuri |
| author_facet | Avishek Ganguly Soumya Basu Paramita Chakraborty Shilpak Chatterjee Avijit Sarkar Mitali Chatterjee Soumitra Kumar Choudhuri |
| author_sort | Avishek Ganguly |
| collection | DOAJ |
| 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-acetyl-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. |
| first_indexed | 2024-12-20T20:05:21Z |
| format | Article |
| id | doaj.art-3d68e4d98836460785c6eb86b707ec58 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T20:05:21Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3d68e4d98836460785c6eb86b707ec582022-12-21T19:27:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0156e1125310.1371/journal.pone.0011253Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate.Avishek GangulySoumya BasuParamita ChakrabortyShilpak ChatterjeeAvijit SarkarMitali ChatterjeeSoumitra Kumar ChoudhuriBACKGROUND: 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-acetyl-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.http://europepmc.org/articles/PMC2889820?pdf=render |
| spellingShingle | Avishek Ganguly Soumya Basu Paramita Chakraborty Shilpak Chatterjee Avijit Sarkar Mitali Chatterjee Soumitra Kumar Choudhuri Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC2889820?pdf=render |
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