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 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.


RESULTS
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.


CONCLUSIONS
Our study provides evidence that FeNG, a redox active metal chelate may be a promising new therapeutic agent against drug resistance cancers.
Ganguly
Avishek
A
Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
Basu
Soumya
S
Chakraborty
Paramita
P
Chatterjee
Shilpak
S
Sarkar
Avijit
A
Chatterjee
Mitali
M
Choudhuri
Soumitra Kumar
SK
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet
D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D005978:Glutathione