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  - JOUR
AU  - Andrei, Luca
AU  - Kasas, Sandor
AU  - Ochoa Garrido, Ignacio
AU  - Stanković, Tijana
AU  - Suárez Korsnes, Mónica
AU  - Vaclavikova, Radka
AU  - Assaraf, Yehuda G.
AU  - Pešić, Milica
PY  - 2020
UR  - https://www.sciencedirect.com/science/article/pii/S136876461930055X?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3508
AB  - The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells' characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.
T2  - Drug Resistance Updates
T1  - Advanced technological tools to study multidrug resistance in cancer.
VL  - 48
DO  - 10.1016/j.drup.2019.100658
SP  - 100658
ER  - 

@article{
author = "Andrei, Luca and Kasas, Sandor and Ochoa Garrido, Ignacio and Stanković, Tijana and Suárez Korsnes, Mónica and Vaclavikova, Radka and Assaraf, Yehuda G. and Pešić, Milica",
year = "2020",
abstract = "The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells' characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.",
journal = "Drug Resistance Updates",
title = "Advanced technological tools to study multidrug resistance in cancer.",
volume = "48",
doi = "10.1016/j.drup.2019.100658",
pages = "100658"
}

Andrei, L., Kasas, S., Ochoa Garrido, I., Stanković, T., Suárez Korsnes, M., Vaclavikova, R., Assaraf, Y. G.,& Pešić, M.. (2020). Advanced technological tools to study multidrug resistance in cancer.. in Drug Resistance Updates, 48, 100658.
https://doi.org/10.1016/j.drup.2019.100658

Andrei L, Kasas S, Ochoa Garrido I, Stanković T, Suárez Korsnes M, Vaclavikova R, Assaraf YG, Pešić M. Advanced technological tools to study multidrug resistance in cancer.. in Drug Resistance Updates. 2020;48:100658.
doi:10.1016/j.drup.2019.100658 .

Andrei, Luca, Kasas, Sandor, Ochoa Garrido, Ignacio, Stanković, Tijana, Suárez Korsnes, Mónica, Vaclavikova, Radka, Assaraf, Yehuda G., Pešić, Milica, "Advanced technological tools to study multidrug resistance in cancer." in Drug Resistance Updates, 48 (2020):100658,
https://doi.org/10.1016/j.drup.2019.100658 . .

TY  - JOUR
AU  - Jovanović, Mirna
AU  - Zhukovsky, Daniil
AU  - Podolski-Renić, Ana
AU  - Domračeva, Ilona
AU  - Žalubovskis, Raivis
AU  - Senćanski, Milan
AU  - Glišić, Sanja
AU  - Sharoyko, Vladimir
AU  - Tennikova, Tatiana
AU  - Dar'in, Dmitry
AU  - Pešić, Milica
AU  - Krasavin, Mikhail
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0223523419307147?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3488
AB  - A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.
T2  - European Journal of Medicinal Chemistry
T1  - Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.
VL  - 181
DO  - 10.1016/j.ejmech.2019.111580
SP  - 111580
ER  - 

@article{
author = "Jovanović, Mirna and Zhukovsky, Daniil and Podolski-Renić, Ana and Domračeva, Ilona and Žalubovskis, Raivis and Senćanski, Milan and Glišić, Sanja and Sharoyko, Vladimir and Tennikova, Tatiana and Dar'in, Dmitry and Pešić, Milica and Krasavin, Mikhail",
year = "2019",
abstract = "A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.",
journal = "European Journal of Medicinal Chemistry",
title = "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.",
volume = "181",
doi = "10.1016/j.ejmech.2019.111580",
pages = "111580"
}

Jovanović, M., Zhukovsky, D., Podolski-Renić, A., Domračeva, I., Žalubovskis, R., Senćanski, M., Glišić, S., Sharoyko, V., Tennikova, T., Dar'in, D., Pešić, M.,& Krasavin, M.. (2019). Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry, 181, 111580.
https://doi.org/10.1016/j.ejmech.2019.111580

Jovanović M, Zhukovsky D, Podolski-Renić A, Domračeva I, Žalubovskis R, Senćanski M, Glišić S, Sharoyko V, Tennikova T, Dar'in D, Pešić M, Krasavin M. Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry. 2019;181:111580.
doi:10.1016/j.ejmech.2019.111580 .

Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Domračeva, Ilona, Žalubovskis, Raivis, Senćanski, Milan, Glišić, Sanja, Sharoyko, Vladimir, Tennikova, Tatiana, Dar'in, Dmitry, Pešić, Milica, Krasavin, Mikhail, "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy." in European Journal of Medicinal Chemistry, 181 (2019):111580,
https://doi.org/10.1016/j.ejmech.2019.111580 . .