Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate

PLoS One. 2010 Jun 22;5(6):e11253. doi: 10.1371/journal.pone.0011253.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • Glutathione / metabolism
  • Humans
  • Hydrolysis
  • Iron Chelating Agents / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism
  • Spectrophotometry, Infrared
  • Spectrophotometry, Ultraviolet

Substances

  • Iron Chelating Agents
  • Reactive Oxygen Species
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Glutathione