ABSTRACT
Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.
Subject(s)
Fibroblasts , Iron , Lipofuscin , Lysosomes , Oxidative Stress , Reactive Oxygen Species , Serine , Humans , Lysosomes/metabolism , Lysosomes/drug effects , Lipofuscin/metabolism , Iron/metabolism , Fibroblasts/metabolism , Fibroblasts/drug effects , Fibroblasts/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Serine/metabolism , Mitochondria/metabolism , Mitochondria/drug effects , Mitochondria/pathology , Neuroaxonal Dystrophies/metabolism , Neuroaxonal Dystrophies/pathology , Neuroaxonal Dystrophies/drug therapy , Neuroaxonal Dystrophies/genetics , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/analogs & derivatives , Iron Chelating Agents/pharmacologyABSTRACT
In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.
Subject(s)
2,2'-Dipyridyl , Antineoplastic Agents , Phosphines , Silver , Humans , Phosphines/chemistry , Phosphines/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Silver/chemistry , Silver/pharmacology , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Cell Line, Tumor , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Apoptosis/drug effects , Crystallography, X-Ray , Ligands , Cell Death/drug effects , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Drug Resistance, Neoplasm/drug effectsABSTRACT
The iron chelator o-phenanthroline enhances the lethal effect of H2O2 about four hundred times in Escherichia coli when both substances are added simultaneously to the culture mediu. If o-phenanthroline is added for increasing periods of time prior to the addition of H2O2, there is a shift from this lethal interaction to protection by the chelator about seven hundred times. It is known that the Fe2+ -o-phenanthroline(I) and Fe2+ -o-phenanthroline(II) complexes are formed quickly whereas the final and more stable Fe2+ -o-phenanthroline(III) complex is formed slowly, Moreover, the mono and bis complexes react with H2O2 to produce OH., whereas the tris complex is stable towards H2O2. Therefore, the lethal effect could be explained by the kinetics of reaction of o-phenanthroline with intracellular Fe2+, i.e., the mono and bis complexes are more reactive than intracellular Fe2+