Genome-wide CRISPR Screen Reveal Targets of Chiral Gold(I) Anticancer Compound in Mammalian Cells.
Jong Hyun KimSamuel OforiAbderrahmane TagmountChristopher D VulpeSamuel G AwuahPublished in: ACS omega (2022)
Metal-based drugs, such as cisplatin and auranofin, are used for the treatment of cancer and rheumatoid arthritis, respectively. Auranofin and other gold-derived compounds have been shown to possess anticancer, anti-inflammatory, antimicrobial, and antiparasitic activity in preclinical and clinical trials. Unlike platinum agents which are known to target DNA, the target of gold is not well elucidated. To better understand the targets and effects of gold agents in mammalian cells, we used a targeted CRISPR (ToxCRISPR) screen in K562 cancer cells to identify genes that modulate cellular sensitivity to gold. We synthesized a novel chiral gold(I) compound, JHK-21, with potent anticancer activity. Among the most sensitizing hits were proteins involved in mitochondrial carriers, mitochondrial metabolism, and oxidative phosphorylation. Further analysis revealed that JHK-21 induced inner mitochondria membrane dysfunction and modulated ATP-binding cassette subfamily member C (ABCC1) function in a manner distinct from auranofin. Characterizing the therapeutic effects and toxicities of metallodrugs in mammalian cells is of growing interest to guide future drug discovery, and cellular and preclinical/clinical studies.
Keyphrases
- genome wide
- rheumatoid arthritis
- oxidative stress
- clinical trial
- drug discovery
- dna methylation
- anti inflammatory
- silver nanoparticles
- crispr cas
- genome editing
- high throughput
- staphylococcus aureus
- randomized controlled trial
- mesenchymal stem cells
- bone marrow
- single cell
- systemic lupus erythematosus
- transcription factor
- high glucose
- disease activity
- cell therapy
- papillary thyroid
- mass spectrometry
- cell free
- phase ii
- single molecule
- protein kinase
- endothelial cells
- ionic liquid
- open label
- idiopathic pulmonary fibrosis
- double blind
- circulating tumor cells