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  - JOUR
AU  - Alexa-Stratulat, Teodora
AU  - Pešić, Milica
AU  - Čipak Gašparović, Ana
AU  - Trougakos, Ioannis
AU  - Riganti, Chiara
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S1368764619300329?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4642
AB  - Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity – i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR.
After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.
PB  - Amsterdam : Elsevier Ltd
T2  - Drug Resistance Updates
T1  - What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg
VL  - 46
DO  - 10.1016/j.drup.2019.100643
SP  - 100643
ER  - 

@article{
author = "Alexa-Stratulat, Teodora and Pešić, Milica and Čipak Gašparović, Ana and Trougakos, Ioannis and Riganti, Chiara",
year = "2019",
abstract = "Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity – i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR.
After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.",
publisher = "Amsterdam : Elsevier Ltd",
journal = "Drug Resistance Updates",
title = "What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg",
volume = "46",
doi = "10.1016/j.drup.2019.100643",
pages = "100643"
}

Alexa-Stratulat, T., Pešić, M., Čipak Gašparović, A., Trougakos, I.,& Riganti, C.. (2019). What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg. in Drug Resistance Updates
Amsterdam : Elsevier Ltd., 46, 100643.
https://doi.org/10.1016/j.drup.2019.100643

Alexa-Stratulat T, Pešić M, Čipak Gašparović A, Trougakos I, Riganti C. What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg. in Drug Resistance Updates. 2019;46:100643.
doi:10.1016/j.drup.2019.100643 .

Alexa-Stratulat, Teodora, Pešić, Milica, Čipak Gašparović, Ana, Trougakos, Ioannis, Riganti, Chiara, "What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg" in Drug Resistance Updates, 46 (2019):100643,
https://doi.org/10.1016/j.drup.2019.100643 . .