A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors
2022
Аутори
Alov, PetkoAl Sharif, Merilin
Aluani, Denitsa
Chegaev, Konstantin
Dinić, Jelena
Divac Rankov, Aleksandra
Fernandes, Miguel X.
Fusi, Fabio
Garcia-Sosa, Alfonso T.
Juvonen, Risto
Kondeva-Burdina, Magdalena
Padron, Jose M.
Pajeva, Ilza
Pencheva, Tania
Puerta, Adrian
Raunio, Hannu
Riganti, Chiara
Tsakovska, Ivanka
Tzankova, Virginia
Yordanov, Yordan
Saponara, Simona
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 p...ercentage 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.
Кључне речи:
zebrafish / P-glycoprotein / off-targets / in silico profiling / hERG / hepatotoxicity / doxorubicin / cytochrome P450Извор:
Frontiers in Pharmacology, 2022, 13Издавач:
- Frontiers Media Sa, Lausanne
Финансирање / пројекти:
- National Science Fund of Bulgaria [KP-06-COST/3/2019, KP-06-COST/1/18.8.2021]
- Haridus-ja Teadusministeerium [IUT34-14]
- Spanish Government (MCIU/AEI/FEDER, UE) [PGC 2018-094503-B-C22]
- University of Siena (F-Lab project 2019)
- Estonian Ministry of Education and Research [IUT34-14]
- European Union European Regional Development Fund through Foundation Archimedes [TK143]
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
DOI: 10.3389/fphar.2022.831791
ISSN: 1663-9812
WoS: 000784200700001
Scopus: 2-s2.0-85127391690
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Alov, Petko AU - Al Sharif, Merilin AU - Aluani, Denitsa AU - Chegaev, Konstantin AU - Dinić, Jelena AU - Divac Rankov, Aleksandra AU - Fernandes, Miguel X. AU - Fusi, Fabio AU - Garcia-Sosa, Alfonso T. AU - Juvonen, Risto AU - Kondeva-Burdina, Magdalena AU - Padron, Jose M. AU - Pajeva, Ilza AU - Pencheva, Tania AU - Puerta, Adrian AU - Raunio, Hannu AU - Riganti, Chiara AU - Tsakovska, Ivanka AU - Tzankova, Virginia AU - Yordanov, Yordan AU - Saponara, Simona PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1555 AB - 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. PB - Frontiers Media Sa, Lausanne T2 - Frontiers in Pharmacology T1 - A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors VL - 13 DO - 10.3389/fphar.2022.831791 ER -
@article{ author = "Alov, Petko and Al Sharif, Merilin and Aluani, Denitsa and Chegaev, Konstantin and Dinić, Jelena and Divac Rankov, Aleksandra and Fernandes, Miguel X. and Fusi, Fabio and Garcia-Sosa, Alfonso T. and Juvonen, Risto and Kondeva-Burdina, Magdalena and Padron, Jose M. and Pajeva, Ilza and Pencheva, Tania and Puerta, Adrian and Raunio, Hannu and Riganti, Chiara and Tsakovska, Ivanka and Tzankova, Virginia and Yordanov, Yordan and Saponara, Simona", year = "2022", abstract = "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.", publisher = "Frontiers Media Sa, Lausanne", journal = "Frontiers in Pharmacology", title = "A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors", volume = "13", doi = "10.3389/fphar.2022.831791" }
Alov, P., Al Sharif, M., Aluani, D., Chegaev, K., Dinić, J., Divac Rankov, A., Fernandes, M. X., Fusi, F., Garcia-Sosa, A. T., Juvonen, R., Kondeva-Burdina, M., Padron, J. M., Pajeva, I., Pencheva, T., Puerta, A., Raunio, H., Riganti, C., Tsakovska, I., Tzankova, V., Yordanov, Y.,& Saponara, S.. (2022). A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors. in Frontiers in Pharmacology Frontiers Media Sa, Lausanne., 13. https://doi.org/10.3389/fphar.2022.831791
Alov P, Al Sharif M, Aluani D, Chegaev K, Dinić J, Divac Rankov A, Fernandes MX, Fusi F, Garcia-Sosa AT, Juvonen R, Kondeva-Burdina M, Padron JM, Pajeva I, Pencheva T, Puerta A, Raunio H, Riganti C, Tsakovska I, Tzankova V, Yordanov Y, Saponara S. A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors. in Frontiers in Pharmacology. 2022;13. doi:10.3389/fphar.2022.831791 .
Alov, Petko, Al Sharif, Merilin, Aluani, Denitsa, Chegaev, Konstantin, Dinić, Jelena, Divac Rankov, Aleksandra, Fernandes, Miguel X., Fusi, Fabio, Garcia-Sosa, Alfonso T., Juvonen, Risto, Kondeva-Burdina, Magdalena, Padron, Jose M., Pajeva, Ilza, Pencheva, Tania, Puerta, Adrian, Raunio, Hannu, Riganti, Chiara, Tsakovska, Ivanka, Tzankova, Virginia, Yordanov, Yordan, Saponara, Simona, "A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors" in Frontiers in Pharmacology, 13 (2022), https://doi.org/10.3389/fphar.2022.831791 . .