TY  - 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  - García-Sosa, Alfonso T.
AU  - Juvonen, Risto
AU  - Kondeva-Burdina, Magdalena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Pencheva, Tania
AU  - Puerta, Adrián
AU  - Raunio, Hannu
AU  - Riganti, Chiara
AU  - Tsakovska, Ivanka
AU  - Tzankova, Virginia
AU  - Yordanov, Yordan
AU  - Saponara, Simona
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4870
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  - Lausanne : Frontiers Media
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
SP  - 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 García-Sosa, Alfonso T. and Juvonen, Risto and Kondeva-Burdina, Magdalena and Padrón, José M. and Pajeva, Ilza and Pencheva, Tania and Puerta, Adrián 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 = "Lausanne : Frontiers Media",
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",
pages = "831791"
}

Alov, P., Al Sharif, M., Aluani, D., Chegaev, K., Dinić, J., Divac Rankov, A., Fernandes, M. X., Fusi, F., García-Sosa, A. T., Juvonen, R., Kondeva-Burdina, M., Padrón, 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
Lausanne : Frontiers Media., 13, 831791.
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, García-Sosa AT, Juvonen R, Kondeva-Burdina M, Padrón 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;13:831791.
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, 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, "A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors" in Frontiers in Pharmacology, 13 (2022):831791,
https://doi.org/10.3389/fphar.2022.831791 . .

TY  - CONF
AU  - Pajeva, Ilza
AU  - Tsakovska, Ivanka
AU  - Alov, Petko
AU  - Pencheva, Tania
AU  - Lessigiarskaa, Iglika
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Musso, Loana
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2020
UR  - https://stratagem-cost.eu/wp-content/uploads/2020/03/Abstract-book-Belgrade-2020.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6498
AB  - Heat Shock Protein 90 (Hsp90) is an ATP-dependent molecular chaperone which interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents because of their limitations in physicochemical properties, safety profiles and efflux by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). In the efforts to develop dual targeting molecules with potential to act against both, deregulated cancer metabolism by Hsp90 inhibition and MDR mechanism by P-gp inhibition, eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in sensitive
and corresponding resistant cancer cells with P-gp overexpression [1]. Three compounds were identified as dual Hsp90 and P-gp inhibitors. This presentation describes in silico studies that were undertaken to elucidate possible interactions of the dual inhibitors with P-gp. In particular, docking simulations were performed using the recently resolved structures of the human P-gp extracted from Protein Data Bank (www.rcsb.org). These structures provide an excellent opportunity for comparison of substrate- and inhibitor-bound structures in the drug-binding cavity of P-gp [2]. Different docking protocols were compared and the one with the best performance on re-docking of the X-ray taxol and zosuquidar structures was selected in terms of: (i) similarity between the generated poses and the corresponding structures in the crystal complex, and (ii) calculated scores, that approximate the binding affinity. The P-gp-ligand interactions were analyzed to outline key residues potentially involved in binding. Based on the results, it was suggested that the binding sites of the studied compounds may partially overlap with a binding site of the P-gp substrate Rhodamine 123, implying that these compounds may act as its competitive inhibitors. The in silico results are in accordance with the experimental findings and contribute to the elucidation of the mechanism action of the dual inhibitors.
PB  - COST Action CA17104
C3  - Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia
T1  - In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp
SP  - 49
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6498
ER  - 

@conference{
author = "Pajeva, Ilza and Tsakovska, Ivanka and Alov, Petko and Pencheva, Tania and Lessigiarskaa, Iglika and Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Musso, Loana and Dallavalle, Sabrina and Pešić, Milica",
year = "2020",
abstract = "Heat Shock Protein 90 (Hsp90) is an ATP-dependent molecular chaperone which interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents because of their limitations in physicochemical properties, safety profiles and efflux by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). In the efforts to develop dual targeting molecules with potential to act against both, deregulated cancer metabolism by Hsp90 inhibition and MDR mechanism by P-gp inhibition, eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in sensitive
and corresponding resistant cancer cells with P-gp overexpression [1]. Three compounds were identified as dual Hsp90 and P-gp inhibitors. This presentation describes in silico studies that were undertaken to elucidate possible interactions of the dual inhibitors with P-gp. In particular, docking simulations were performed using the recently resolved structures of the human P-gp extracted from Protein Data Bank (www.rcsb.org). These structures provide an excellent opportunity for comparison of substrate- and inhibitor-bound structures in the drug-binding cavity of P-gp [2]. Different docking protocols were compared and the one with the best performance on re-docking of the X-ray taxol and zosuquidar structures was selected in terms of: (i) similarity between the generated poses and the corresponding structures in the crystal complex, and (ii) calculated scores, that approximate the binding affinity. The P-gp-ligand interactions were analyzed to outline key residues potentially involved in binding. Based on the results, it was suggested that the binding sites of the studied compounds may partially overlap with a binding site of the P-gp substrate Rhodamine 123, implying that these compounds may act as its competitive inhibitors. The in silico results are in accordance with the experimental findings and contribute to the elucidation of the mechanism action of the dual inhibitors.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia",
title = "In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp",
pages = "49",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6498"
}

Pajeva, I., Tsakovska, I., Alov, P., Pencheva, T., Lessigiarskaa, I., Dinić, J., Podolski-Renić, A., Jovanović, M., Musso, L., Dallavalle, S.,& Pešić, M.. (2020). In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia
COST Action CA17104., 49.
https://hdl.handle.net/21.15107/rcub_ibiss_6498

Pajeva I, Tsakovska I, Alov P, Pencheva T, Lessigiarskaa I, Dinić J, Podolski-Renić A, Jovanović M, Musso L, Dallavalle S, Pešić M. In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia. 2020;:49.
https://hdl.handle.net/21.15107/rcub_ibiss_6498 .

Pajeva, Ilza, Tsakovska, Ivanka, Alov, Petko, Pencheva, Tania, Lessigiarskaa, Iglika, Dinić, Jelena, Podolski-Renić, Ana, Jovanović, Mirna, Musso, Loana, Dallavalle, Sabrina, Pešić, Milica, "In silico study to elucidate possible interactions of Hsp90 inhibitors with P-gp" in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia (2020):49,
https://hdl.handle.net/21.15107/rcub_ibiss_6498 .