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  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Tsakovska, Ivanka
AU  - Pajeva, Ilza
AU  - Tuccinardi, Tiziano
AU  - Botta, Lorenzo
AU  - Schenone, Silvia
AU  - Pešić, Milica
PY  - 2021
UR  - https://www.mdpi.com/2072-6694/13/21/5308
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4631
AB  - Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P‐glycoprotein (P‐gp) is the most com-mon alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4‐d]pyrimidines on P‐gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non‐small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P‐gp and inhibited its ATPase activity. Their potential P‐gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration‐dependent manner. The expression studies excluded the indirect effect of TKIs on P‐gp through regulation of its expression. A kinetics study showed that TKIs decreased P‐gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4‐d]pyrimidines with potential for reversing P‐gp‐mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.
PB  - Basel: MDPI
T2  - Cancers
T1  - New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors
IS  - 21
VL  - 13
DO  - 10.3390/cancers13215308
SP  - 5308
ER  - 

@article{
author = "Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Tsakovska, Ivanka and Pajeva, Ilza and Tuccinardi, Tiziano and Botta, Lorenzo and Schenone, Silvia and Pešić, Milica",
year = "2021",
abstract = "Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P‐glycoprotein (P‐gp) is the most com-mon alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4‐d]pyrimidines on P‐gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non‐small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P‐gp and inhibited its ATPase activity. Their potential P‐gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration‐dependent manner. The expression studies excluded the indirect effect of TKIs on P‐gp through regulation of its expression. A kinetics study showed that TKIs decreased P‐gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4‐d]pyrimidines with potential for reversing P‐gp‐mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.",
publisher = "Basel: MDPI",
journal = "Cancers",
title = "New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors",
number = "21",
volume = "13",
doi = "10.3390/cancers13215308",
pages = "5308"
}

Podolski-Renić, A., Dinić, J., Stanković, T., Tsakovska, I., Pajeva, I., Tuccinardi, T., Botta, L., Schenone, S.,& Pešić, M.. (2021). New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors. in Cancers
Basel: MDPI., 13(21), 5308.
https://doi.org/10.3390/cancers13215308

Podolski-Renić A, Dinić J, Stanković T, Tsakovska I, Pajeva I, Tuccinardi T, Botta L, Schenone S, Pešić M. New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors. in Cancers. 2021;13(21):5308.
doi:10.3390/cancers13215308 .

Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Tsakovska, Ivanka, Pajeva, Ilza, Tuccinardi, Tiziano, Botta, Lorenzo, Schenone, Silvia, Pešić, Milica, "New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors" in Cancers, 13, no. 21 (2021):5308,
https://doi.org/10.3390/cancers13215308 . .

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 .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Efferth, Thomas
AU  - García-Sosa, Alfonso T.
AU  - Grahovac, Jelena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Rizzolio, Flavio
AU  - Saponara, Simona
AU  - Spengler, Gabriella
AU  - Tsakovska, Ivanka
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3758
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3767
AB  - Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.
PB  - Churchill Livingstone
T2  - Drug Resistance Updates
T1  - Repurposing old drugs to fight multidrug resistant cancers
VL  - 52
DO  - 10.1016/j.drup.2020.100713
SP  - 100713
ER  - 

@article{
author = "Dinić, Jelena and Efferth, Thomas and García-Sosa, Alfonso T. and Grahovac, Jelena and Padrón, José M. and Pajeva, Ilza and Rizzolio, Flavio and Saponara, Simona and Spengler, Gabriella and Tsakovska, Ivanka",
year = "2020",
abstract = "Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.",
publisher = "Churchill Livingstone",
journal = "Drug Resistance Updates",
title = "Repurposing old drugs to fight multidrug resistant cancers",
volume = "52",
doi = "10.1016/j.drup.2020.100713",
pages = "100713"
}

Dinić, J., Efferth, T., García-Sosa, A. T., Grahovac, J., Padrón, J. M., Pajeva, I., Rizzolio, F., Saponara, S., Spengler, G.,& Tsakovska, I.. (2020). Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates
Churchill Livingstone., 52, 100713.
https://doi.org/10.1016/j.drup.2020.100713

Dinić J, Efferth T, García-Sosa AT, Grahovac J, Padrón JM, Pajeva I, Rizzolio F, Saponara S, Spengler G, Tsakovska I. Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates. 2020;52:100713.
doi:10.1016/j.drup.2020.100713 .

Dinić, Jelena, Efferth, Thomas, García-Sosa, Alfonso T., Grahovac, Jelena, Padrón, José M., Pajeva, Ilza, Rizzolio, Flavio, Saponara, Simona, Spengler, Gabriella, Tsakovska, Ivanka, "Repurposing old drugs to fight multidrug resistant cancers" in Drug Resistance Updates, 52 (2020):100713,
https://doi.org/10.1016/j.drup.2020.100713 . .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Efferth, Thomas
AU  - García-Sosa, Alfonso T.
AU  - Grahovac, Jelena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Rizzolio, Flavio
AU  - Saponara, Simona
AU  - Spengler, Gabriella
AU  - Tsakovska, Ivanka
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3758
AB  - Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.
PB  - Churchill Livingstone
T2  - Drug Resistance Updates
T1  - Repurposing old drugs to fight multidrug resistant cancers
VL  - 52
DO  - 10.1016/j.drup.2020.100713
SP  - 100713
ER  - 

@article{
author = "Dinić, Jelena and Efferth, Thomas and García-Sosa, Alfonso T. and Grahovac, Jelena and Padrón, José M. and Pajeva, Ilza and Rizzolio, Flavio and Saponara, Simona and Spengler, Gabriella and Tsakovska, Ivanka",
year = "2020",
abstract = "Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.",
publisher = "Churchill Livingstone",
journal = "Drug Resistance Updates",
title = "Repurposing old drugs to fight multidrug resistant cancers",
volume = "52",
doi = "10.1016/j.drup.2020.100713",
pages = "100713"
}

Dinić, J., Efferth, T., García-Sosa, A. T., Grahovac, J., Padrón, J. M., Pajeva, I., Rizzolio, F., Saponara, S., Spengler, G.,& Tsakovska, I.. (2020). Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates
Churchill Livingstone., 52, 100713.
https://doi.org/10.1016/j.drup.2020.100713

Dinić J, Efferth T, García-Sosa AT, Grahovac J, Padrón JM, Pajeva I, Rizzolio F, Saponara S, Spengler G, Tsakovska I. Repurposing old drugs to fight multidrug resistant cancers. in Drug Resistance Updates. 2020;52:100713.
doi:10.1016/j.drup.2020.100713 .

Dinić, Jelena, Efferth, Thomas, García-Sosa, Alfonso T., Grahovac, Jelena, Padrón, José M., Pajeva, Ilza, Rizzolio, Flavio, Saponara, Simona, Spengler, Gabriella, Tsakovska, Ivanka, "Repurposing old drugs to fight multidrug resistant cancers" in Drug Resistance Updates, 52 (2020):100713,
https://doi.org/10.1016/j.drup.2020.100713 . .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Musso, Loana
AU  - Tsakovska, Ivanka
AU  - Pajeva, Ilza
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - https://www.mdpi.com/1422-0067/20/18/4575
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3476
AB  - Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.
T2  - International Journal of Molecular Sciences
T1  - Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.
IS  - 18
VL  - 20
DO  - 10.3390/ijms20184575
SP  - 4575
ER  - 

@article{
author = "Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Musso, Loana and Tsakovska, Ivanka and Pajeva, Ilza and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.",
journal = "International Journal of Molecular Sciences",
title = "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.",
number = "18",
volume = "20",
doi = "10.3390/ijms20184575",
pages = "4575"
}

Dinić, J., Podolski-Renić, A., Jovanović, M., Musso, L., Tsakovska, I., Pajeva, I., Dallavalle, S.,& Pešić, M.. (2019). Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences, 20(18), 4575.
https://doi.org/10.3390/ijms20184575

Dinić J, Podolski-Renić A, Jovanović M, Musso L, Tsakovska I, Pajeva I, Dallavalle S, Pešić M. Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences. 2019;20(18):4575.
doi:10.3390/ijms20184575 .

Dinić, Jelena, Podolski-Renić, Ana, Jovanović, Mirna, Musso, Loana, Tsakovska, Ivanka, Pajeva, Ilza, Dallavalle, Sabrina, Pešić, Milica, "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells." in International Journal of Molecular Sciences, 20, no. 18 (2019):4575,
https://doi.org/10.3390/ijms20184575 . .