TY - JOUR
T1 - Benefits and toxicity of disulfiram in preclinical models of nephropathic cystinosis
AU - Taranta, Anna
AU - Elmonem, Mohamed A.
AU - Bellomo, Francesco
AU - De Leo, Ester
AU - Boenzi, Sara
AU - Janssen, Manoe J.
AU - Jamalpoor, Amer
AU - Cairoli, Sara
AU - Pastore, Anna
AU - De Stefanis, Cristiano
AU - Colucci, Manuela
AU - Rega, Laura R.
AU - Giovannoni, Isabella
AU - Francalanci, Paola
AU - van den Heuvel, Lambertus P.
AU - Dionisi-Vici, Carlo
AU - Goffredo, Bianca M.
AU - Masereeuw, Rosalinde
AU - Levtchenko, Elena
AU - Emma, Francesco
N1 - Funding Information: Funding: This research was funded by the Cystinosis Research Foundation (grant no. CRFS-2014), the Italian Ministry of Health (Ricerca Corrente grant no. RC2015), E-rare European Union (grant no. E-Rare-2 JTC 2014), and the Foundation of Scientific Research Flanders (award 11Y5216N). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Cystinosis
KW - Disulfiram
KW - Mice
KW - Zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85119679534&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells10123294
DO - https://doi.org/10.3390/cells10123294
M3 - Article
C2 - 34943802
SN - 2073-4409
VL - 10
JO - Cells
JF - Cells
IS - 12
M1 - 3294
ER -