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. 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 ne

Phosphorus-31, cadmium-111, cadmium-113 and mercury-199 N.M.R. studies of cadmium(II) halide and mixed cadmium(II)-mercury(II) halide complexes with tributylphosphine

Phosphorus-31, cadmium-111 and cadmium-113 n.m.r, studies have been carried out on CdX2(PBu3)2 (where X = Cl, Br, I). The results are consistent with exchange of both phosphine and halogen. Phosphine exchange becomes slow on the N.M.R. time scale in all cases by -40°C. Mixtures of CdX2(PBu3)2 with different halogens give averaged signals at room temperature, but below about -80°C exchange becomes slow and halogen redistribution reactions can be observed. ��� Reaction of CdX2 and PBu3 in 1 : 1 proportions in ethanol gives Cd2X4(PBu3)3 as the isolated product, not Cd2X4(PBu3)2. It is shown that ethanol is an effective ligand to cadmium and redistribution reactions between coordinated ethanol and the phosphine occur. ��� The mixed metal complexes CdHgX4(PBu3)2 have been shown by phosphorus-31, cadmium-113 and mercury-199 n.m.r, studies to have all the phosphine coordinated to mercury. ��� Cadmium-111 and cadmium-113 chemical shifts in these compounds span a range of over 500 ppm and shifts have been correlated with 31P chemical shifts and the coupling constant JP,Cd.</jats:p

Phosphorus-31, mercury-199 and selenium-77 n.m.r. studies of ligand exchange reactions in mercury(II) halide complexes

Mercury(II) halide complexes of tris(4-methoxyphenyl)phosphine have been investigated by 31P and 199Hg n.m.r. spectroscopy of CH2Cl2 solutions. At room temperature the phosphine exchanges at an appreciable rate and halogen exchange is fast. At -50°C both phosphine and halogen exchange are slow on the n.m.r. time scale and halogen redistribution reactions are observed. ��� Mercury(II) halide complexes with tributylphosphine selenide have been investigated by 31P, 199Hg and 77Se n.m.r. methods. This ligand is labile and exchanges rapidly on the n.m.r. time scale at room temperature, although the exchange can be slowed down at about -100°C. Halogen exchange is also fast at room temperature. ��� Ligand exchange reactions between tributylphosphine and either tris(4-methoxyphenyl)phosphine or tributylphosphine selenide were investigated and redistribution reactions to give mixed ligand complexes were observed.</jats:p