A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors
2022
Authors:
Alov, PetkoAl Sharif, Merilin
Aluani, Denitsa
Chegaev, Konstantin
Dinić, Jelena
Divac Rankov, Aleksandra
Fernandes, Miguel X.
Fusi, Fabio
García-Sosa, Alfonso T.
Juvonen, Risto
Kondeva-Burdina, Magdalena
Padrón, José M.
Pajeva, Ilza
Pencheva, Tania
Puerta, Adrián
Raunio, Hannu
Riganti, Chiara
Tsakovska, Ivanka
Tzankova, Virginia
Yordanov, Yordan
Saponara, Simona
Document Type:
Article (Published version)
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© 2022 Alov, Al Sharif, Aluani, Chegaev, Dinic, Divac Rankov, Fernandes, Fusi, García-Sosa, Juvonen, Kondeva-Burdina, Padrón, Pajeva, Pencheva, Puerta, Raunio, Riganti, Tsakovska, Tzankova, Yordanov and Saponara.
Metadata
Show full item recordAbstract:
Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.
Keywords:
cytochrome P450; doxorubicin; hepatotoxicity; hERG; in silico profiling; off-targets; P-glycoprotein; zebrafishSource:
Frontiers in Pharmacology, 2022, 13, 831791-Funding / projects:
- National Science Fund of Bulgaria (grant KP-06-COST/3/2019)
- National Science Fund of Bulgaria (grant KP-06-COST/1/18.8.2021)
- Haridus-ja Teadusministeerium (grant IUT34-14)
- Spanish Government (Project PGC 2018-094503-B-C22, MCIU/AEI/FEDER, UE)
- University of Siena (F-Lab project 2019)
- Estonian Ministry of Education and Research (grant IUT34-14)
- European Union European Regional Development Fund through Foundation Archimedes (grant TK143, Centre of Excellence in Molecular Cell Engineering)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200042 (University of Belgrade, Institute of Molecular Genetics and Genetic Engineering) (RS-MESTD-inst-2020-200042)