PUBLICATION
Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis
- Authors
- Taranta, A., Elmonem, M.A., Bellomo, F., De Leo, E., Boenzi, S., Janssen, M.J., Jamalpoor, A., Cairoli, S., Pastore, A., De Stefanis, C., Colucci, M., Rega, L.R., Giovannoni, I., Francalanci, P., van den Heuvel, L.P., Dionisi-Vici, C., Goffredo, B.M., Masereeuw, R., Levtchenko, E., Emma, F.
- ID
- ZDB-PUB-211230-8
- Date
- 2021
- Source
- Cells 10(12): (Journal)
- Registered Authors
- Keywords
- cystinosis, disulfiram, mice, zebrafish
- MeSH Terms
-
- Cystine/metabolism
- Toxicity Tests*
- Kidney Diseases/pathology*
- Kidney Diseases/urine
- Cystinosis/pathology*
- Cystinosis/urine
- Disulfides/metabolism
- Embryo, Nonmammalian/metabolism
- Apoptosis
- Humans
- Zebrafish/embryology
- Disulfiram/chemistry
- Disulfiram/toxicity*
- Acetylcysteine/pharmacology
- Animals
- Disease Models, Animal
- Mice, Knockout
- Larva/metabolism
- PubMed
- 34943802 Full text @ Cells
Citation
Taranta, A., Elmonem, M.A., Bellomo, F., De Leo, E., Boenzi, S., Janssen, M.J., Jamalpoor, A., Cairoli, S., Pastore, A., De Stefanis, C., Colucci, M., Rega, L.R., Giovannoni, I., Francalanci, P., van den Heuvel, L.P., Dionisi-Vici, C., Goffredo, B.M., Masereeuw, R., Levtchenko, E., Emma, F. (2021) Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis. Cells. 10(12):.
Abstract
Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping