Multitarget-Directed Gallium(III) Tris(acyl-pyrazolonate) Complexes Induce Ferroptosis in Cancer Cells via Dysregulation of Cell Redox Homeostasis and Inhibition of the Mevalonate Pathway.
Daphne RomaniFabio MarchettiCorrado Di NicolaMassimiliano CuccioloniChunmei GongAnna Maria EleuteriAgustı N GalindoFarzaneh Fadaei TiraniMassimo NabissiRiccardo PettinariPublished in: Journal of medicinal chemistry (2023)
A series of Ga(Q n ) 3 coordination compounds have been synthesized, where HQ n is 1-phenyl-3-methyl-4-RC(═O)-pyrazolo-5-one. The complexes have been characterized through analytical data, NMR and IR spectroscopy, ESI mass spectrometry, elemental analysis, X-ray crystallography, and density functional theory (DFT) studies. Cytotoxic activity against a panel of human cancer cell lines was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, with interesting results in terms of both cell line selectivity and toxicity values compared with cisplatin. The mechanism of action was explored by spectrophotometric, fluorometric, chromatographic, immunometric, and cytofluorimetric assays, SPR biosensor binding studies, and cell-based experiments. Cell treatment with gallium(III) complexes promoted several cell death triggering signals (accumulation of p27, PCNA, PARP fragments, activation of the caspase cascade, and inhibition of the mevalonate pathway) and induced changes in cell redox homeostasis (decreased levels of GSH/GPX4 and NADP(H), increased reactive oxygen species (ROS) and 4-hydroxynonenal (HNE), mitochondrial damage, and increased activity of CPR and CcO), identifying ferroptosis as the mechanism responsible for cancer cell death.
Keyphrases
- cell death
- density functional theory
- single cell
- reactive oxygen species
- cell therapy
- high resolution
- mass spectrometry
- oxidative stress
- cell cycle arrest
- high throughput
- stem cells
- squamous cell carcinoma
- molecular dynamics
- magnetic resonance
- dna damage
- cardiac arrest
- gold nanoparticles
- papillary thyroid
- endothelial cells
- ms ms
- computed tomography
- pet ct
- machine learning
- magnetic resonance imaging
- molecular docking
- electronic health record
- childhood cancer
- endoplasmic reticulum stress
- lymph node metastasis
- anti inflammatory