TY  - CONF
AU  - Ljujić, Mila
AU  - Trifunović, Sara
AU  - Ilić, Bojan
AU  - Milovanović, Jelena
AU  - Dinić, Jelena
AU  - Divac Rankov, Aleksandra
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6250
AB  - Introduction: Cigarette smoke exposure is a known risk factor for development of lung diseases and
electronic cigarettes (e-cigarettes) were introduced as a popular and safer alternative to combustible tobacco products. Increasing number of studies are reporting their adverse biological effects both in vivo
and in vitro. Aim of this study was to evaluate the effect of e-cigarettes on mitochondrial function in
lung bronchial epithelial cells.
Methods: Electronic cigarette vapor condensate (ECC) was generated using an e-cigarette device on a
suction trap cooled in a dry ice/ethanol bath. We used unflavoured and flavoured e-cigarette liquids with
and without nicotine. Human bronchial epithelial BEAS2B cells were seeded in 96well plates and treated
with 2% e-cigarette vapour condensate for 24h. Mitochondrial membrane potential was measured using
50nM TMRE (Tetramethyl rhodamine ethyl ester) and cells were visualized on ImageXpress® Pico Automated Cell Imaging System (Molecular Devices, San Jose, CA, USA) with a 10x objective.
Results: We found a significant reduction of TMRE fluorescence in treated cells compared to the control. Imaging of treated cells also revealed changes in cell morphology and the presence of mitochondria in TNT-like structures.
Conclusion: Mitochondrial dysfunction has been associated with various pathological conditions including lung diseases such as asthma, COPD and lung cancer. Due to their relative novelty, the role of
electronic cigarette use in development of chronic lung diseases is still relatively unknown. Our findings
contribute to the growing list of studies pointing to their adverse biological effects and imply their involvement in processes contributing to chronic lung diseases.
PB  - Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
C3  - Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia
T1  - Electronic cigarette vapour condensate affects mitochondrial potential in BEAS2B cells
SP  - 139
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6250
ER  - 

@conference{
author = "Ljujić, Mila and Trifunović, Sara and Ilić, Bojan and Milovanović, Jelena and Dinić, Jelena and Divac Rankov, Aleksandra",
year = "2023",
abstract = "Introduction: Cigarette smoke exposure is a known risk factor for development of lung diseases and
electronic cigarettes (e-cigarettes) were introduced as a popular and safer alternative to combustible tobacco products. Increasing number of studies are reporting their adverse biological effects both in vivo
and in vitro. Aim of this study was to evaluate the effect of e-cigarettes on mitochondrial function in
lung bronchial epithelial cells.
Methods: Electronic cigarette vapor condensate (ECC) was generated using an e-cigarette device on a
suction trap cooled in a dry ice/ethanol bath. We used unflavoured and flavoured e-cigarette liquids with
and without nicotine. Human bronchial epithelial BEAS2B cells were seeded in 96well plates and treated
with 2% e-cigarette vapour condensate for 24h. Mitochondrial membrane potential was measured using
50nM TMRE (Tetramethyl rhodamine ethyl ester) and cells were visualized on ImageXpress® Pico Automated Cell Imaging System (Molecular Devices, San Jose, CA, USA) with a 10x objective.
Results: We found a significant reduction of TMRE fluorescence in treated cells compared to the control. Imaging of treated cells also revealed changes in cell morphology and the presence of mitochondria in TNT-like structures.
Conclusion: Mitochondrial dysfunction has been associated with various pathological conditions including lung diseases such as asthma, COPD and lung cancer. Due to their relative novelty, the role of
electronic cigarette use in development of chronic lung diseases is still relatively unknown. Our findings
contribute to the growing list of studies pointing to their adverse biological effects and imply their involvement in processes contributing to chronic lung diseases.",
publisher = "Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade",
journal = "Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia",
title = "Electronic cigarette vapour condensate affects mitochondrial potential in BEAS2B cells",
pages = "139",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6250"
}

Ljujić, M., Trifunović, S., Ilić, B., Milovanović, J., Dinić, J.,& Divac Rankov, A.. (2023). Electronic cigarette vapour condensate affects mitochondrial potential in BEAS2B cells. in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia
Belgrade: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade., 139.
https://hdl.handle.net/21.15107/rcub_ibiss_6250

Ljujić M, Trifunović S, Ilić B, Milovanović J, Dinić J, Divac Rankov A. Electronic cigarette vapour condensate affects mitochondrial potential in BEAS2B cells. in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia. 2023;:139.
https://hdl.handle.net/21.15107/rcub_ibiss_6250 .

Ljujić, Mila, Trifunović, Sara, Ilić, Bojan, Milovanović, Jelena, Dinić, Jelena, Divac Rankov, Aleksandra, "Electronic cigarette vapour condensate affects mitochondrial potential in BEAS2B cells" in Abstract Book: CoMBoS2 - the Second Congress of Molecular Biologists of Serbia; 2023 Oct 6-8; Belgrade, Serbia (2023):139,
https://hdl.handle.net/21.15107/rcub_ibiss_6250 .

TY  - JOUR
AU  - Divac Rankov, Aleksandra
AU  - Jovanović Stojanov, Sofija
AU  - Dragoj, Miodrag
AU  - Ljujić, Mila
PY  - 2022
UR  - https://link.springer.com/10.1007/s00418-022-02172-3
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5350
AB  - Identification of the signature molecular profiles involved in therapy resistance is of vital importance in developing new strategies for treatments and disease monitoring. Protein alpha-1 antitrypsin (AAT, encoded by SERPINA1 gene) is an acute-phase protein, and its high expression has been linked with unfavorable clinical outcome in different types of cancer; however, data on its involvement in therapy resistance are still insufficient. We analyzed SERPINA1 mRNA expression in three different multidrug-resistant (MDR) cell lines—U87-TxR, NCI-H460/R, and DLD1-TxR—and in U87 cells grown in alginate microfibers as a 3D cellular model of glioblastoma. Expression of IL-6 as a major modulator of SERPINA1 was also analyzed. Additionally, AAT protein expression in MDR cells was analyzed by immunofluorescence. SERPINA1 gene expression and AAT protein expression were significantly upregulated in all the tested MDR cell lines compared with their sensitive counterparts. Moreover, SERPINA1 was significantly upregulated in 3D models of glioblastoma, previously found to have upregulated drug-resistance-related gene expression compared with 2D cells. With the exception of NCI-H460/R, in all cell lines as well as in a 3D model of U87 cells, increase in SERPINA1 expression correlated with the increase in IL-6 expression. Our results indicate that AAT could be utilized as a biomarker of therapy resistance in cancer; however, further studies are needed to elucidate the mechanisms driving AAT upregulation in therapy resistance and its biological significance in this process.
T2  - Histochemistry and Cell Biology
T1  - Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells
DO  - 10.1007/s00418-022-02172-3
ER  - 

@article{
author = "Divac Rankov, Aleksandra and Jovanović Stojanov, Sofija and Dragoj, Miodrag and Ljujić, Mila",
year = "2022",
abstract = "Identification of the signature molecular profiles involved in therapy resistance is of vital importance in developing new strategies for treatments and disease monitoring. Protein alpha-1 antitrypsin (AAT, encoded by SERPINA1 gene) is an acute-phase protein, and its high expression has been linked with unfavorable clinical outcome in different types of cancer; however, data on its involvement in therapy resistance are still insufficient. We analyzed SERPINA1 mRNA expression in three different multidrug-resistant (MDR) cell lines—U87-TxR, NCI-H460/R, and DLD1-TxR—and in U87 cells grown in alginate microfibers as a 3D cellular model of glioblastoma. Expression of IL-6 as a major modulator of SERPINA1 was also analyzed. Additionally, AAT protein expression in MDR cells was analyzed by immunofluorescence. SERPINA1 gene expression and AAT protein expression were significantly upregulated in all the tested MDR cell lines compared with their sensitive counterparts. Moreover, SERPINA1 was significantly upregulated in 3D models of glioblastoma, previously found to have upregulated drug-resistance-related gene expression compared with 2D cells. With the exception of NCI-H460/R, in all cell lines as well as in a 3D model of U87 cells, increase in SERPINA1 expression correlated with the increase in IL-6 expression. Our results indicate that AAT could be utilized as a biomarker of therapy resistance in cancer; however, further studies are needed to elucidate the mechanisms driving AAT upregulation in therapy resistance and its biological significance in this process.",
journal = "Histochemistry and Cell Biology",
title = "Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells",
doi = "10.1007/s00418-022-02172-3"
}

Divac Rankov, A., Jovanović Stojanov, S., Dragoj, M.,& Ljujić, M.. (2022). Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells. in Histochemistry and Cell Biology.
https://doi.org/10.1007/s00418-022-02172-3

Divac Rankov A, Jovanović Stojanov S, Dragoj M, Ljujić M. Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells. in Histochemistry and Cell Biology. 2022;.
doi:10.1007/s00418-022-02172-3 .

Divac Rankov, Aleksandra, Jovanović Stojanov, Sofija, Dragoj, Miodrag, Ljujić, Mila, "Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells" in Histochemistry and Cell Biology (2022),
https://doi.org/10.1007/s00418-022-02172-3 . .

TY  - JOUR
AU  - Trifunović, Sara
AU  - Smiljanić, Katarina
AU  - Sickmann, Albert
AU  - Solari, Fiorella A.
AU  - Kolarević, Stoimir
AU  - Divac Rankov, Aleksandra
AU  - Ljujić, Mila
PY  - 2022
UR  - https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02102-w
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC9285873
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5082
AB  - BACKGROUND Although still considered a safer alternative to classical cigarettes, growing body of work points to harmful effects of electronic cigarettes (e-cigarettes) affecting a range of cellular processes. The biological effect of e-cigarettes needs to be investigated in more detail considering their widespread use. METHODS In this study, we treated V79 lung fibroblasts with sub-cytotoxic concentration of e-cigarette liquids, with and without nicotine. Mutagenicity was evaluated by HPRT assay, genotoxicity by comet assay and the effect on cellular communication by metabolic cooperation assay. Additionally, comprehensive proteome analysis was performed via high resolution, parallel accumulation serial fragmentation-PASEF mass spectrometry. RESULTS E-cigarette liquid concentration used in this study showed no mutagenic or genotoxic effect, however it negatively impacted metabolic cooperation between V79 cells. Both e-cigarette liquids induced significant depletion in total number of proteins and impairment of mitochondrial function in treated cells. The focal adhesion proteins were upregulated, which is in accordance with the results of metabolic cooperation assay. Increased presence of posttranslational modifications (PTMs), including carbonylation and direct oxidative modifications, was observed. Data are available via ProteomeXchange with identifier PXD032071. CONCLUSIONS Our study revealed impairment of metabolic cooperation as well as significant proteome and PTMs alterations in V79 cells treated with e-cigarette liquid warranting future studies on e-cigarettes health impact.
PB  - London: BMC
T2  - Respiratory Research
T1  - Electronic cigarette liquids impair metabolic cooperation and alter proteomic profiles in V79 cells.
IS  - 1
VL  - 23
DO  - 10.1186/s12931-022-02102-w
SP  - 191
ER  - 

@article{
author = "Trifunović, Sara and Smiljanić, Katarina and Sickmann, Albert and Solari, Fiorella A. and Kolarević, Stoimir and Divac Rankov, Aleksandra and Ljujić, Mila",
year = "2022",
abstract = "BACKGROUND Although still considered a safer alternative to classical cigarettes, growing body of work points to harmful effects of electronic cigarettes (e-cigarettes) affecting a range of cellular processes. The biological effect of e-cigarettes needs to be investigated in more detail considering their widespread use. METHODS In this study, we treated V79 lung fibroblasts with sub-cytotoxic concentration of e-cigarette liquids, with and without nicotine. Mutagenicity was evaluated by HPRT assay, genotoxicity by comet assay and the effect on cellular communication by metabolic cooperation assay. Additionally, comprehensive proteome analysis was performed via high resolution, parallel accumulation serial fragmentation-PASEF mass spectrometry. RESULTS E-cigarette liquid concentration used in this study showed no mutagenic or genotoxic effect, however it negatively impacted metabolic cooperation between V79 cells. Both e-cigarette liquids induced significant depletion in total number of proteins and impairment of mitochondrial function in treated cells. The focal adhesion proteins were upregulated, which is in accordance with the results of metabolic cooperation assay. Increased presence of posttranslational modifications (PTMs), including carbonylation and direct oxidative modifications, was observed. Data are available via ProteomeXchange with identifier PXD032071. CONCLUSIONS Our study revealed impairment of metabolic cooperation as well as significant proteome and PTMs alterations in V79 cells treated with e-cigarette liquid warranting future studies on e-cigarettes health impact.",
publisher = "London: BMC",
journal = "Respiratory Research",
title = "Electronic cigarette liquids impair metabolic cooperation and alter proteomic profiles in V79 cells.",
number = "1",
volume = "23",
doi = "10.1186/s12931-022-02102-w",
pages = "191"
}

Trifunović, S., Smiljanić, K., Sickmann, A., Solari, F. A., Kolarević, S., Divac Rankov, A.,& Ljujić, M.. (2022). Electronic cigarette liquids impair metabolic cooperation and alter proteomic profiles in V79 cells.. in Respiratory Research
London: BMC., 23(1), 191.
https://doi.org/10.1186/s12931-022-02102-w

Trifunović S, Smiljanić K, Sickmann A, Solari FA, Kolarević S, Divac Rankov A, Ljujić M. Electronic cigarette liquids impair metabolic cooperation and alter proteomic profiles in V79 cells.. in Respiratory Research. 2022;23(1):191.
doi:10.1186/s12931-022-02102-w .

Trifunović, Sara, Smiljanić, Katarina, Sickmann, Albert, Solari, Fiorella A., Kolarević, Stoimir, Divac Rankov, Aleksandra, Ljujić, Mila, "Electronic cigarette liquids impair metabolic cooperation and alter proteomic profiles in V79 cells." in Respiratory Research, 23, no. 1 (2022):191,
https://doi.org/10.1186/s12931-022-02102-w . .

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  - Ljujić, Mila
AU  - Divac Rankov, Aleksandra
AU  - Dragoj, Miodrag
AU  - Jovanović Stojanov, Sofija
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5713
AB  - Identification of the signature molecular factors and transcriptional profiles involved in
therapy resistance is of vital importance in developing new strategies for treatments and disease
monitoring. Tumour secretome is a set of macromolecules secreted by tumour cells into the extracellular
space as a response to changes in tumour environment that at the same time shapes the microenvironment
further promoting specific phenotypes and contributing to cellular plasticity in tumour. Protein alpha-1
antitrypsin (AAT, encoded by SERPINA1 gene) is an acute phase protein that has emerged as one of the key
components in tumour secretome involved in crucial stages of tumour development and progression, with
recent data also implicating it in therapeutic resistance. However, what exactly leads to SERPINA1
upregulation during development of therapy resistance, as well as its biological significance in this process,
is still unclear. Our aim was to analyse SERPINA1 expression in multidrug resistant cell lines and 3D cellular
models. Expression of IL-6 was also analysed, as AAT is an acute phase reactant and its levels increase in
response to inflammatory cytokines. Patients and methods: We analysed SERPINA1 and IL-6 expression in
three different cell lines - human glioblastoma U87, non-small cell lung carcinoma NCI-H460 and colorectal
carcinoma DLD1 as well as their multidrug resistant counterparts U87-TxR, NCI-H460/R and DLD1-TxR,
respectively. In addition, expression analysis was performed in long-term 3D glioblastoma model of U87
cells cultured in alginate microfibers, and compared to long-term 2D cell culture of U87. Quantitative RTPCR was performed using Taqman gene expression assays and data were normalized to GAPDH. Results:
We found that SERPINA1 expression is significantly upregulated in all the multidrug resistant cell lines
analysed compared to their sensitive counterparts. Expression of IL-6 was significantly upregulated in U87-
TxR and DLD1-TxR compared to their parental lines, however NCI-H460/R cell line had lower IL-6 expression
compared to NCI-H460. In 3D glioblastoma model of U87 cells, previously found to exhibit increased
therapy resistance compared to 2D cell culture, both SERPINA1 and IL-6 expression were significantly
upregulated. Conclusion: Our results indicate that SERPINA1 expression correlates with therapy resistance
in analysed cell lines and 3D model of glioblastoma, revealing the potential of utilizing this molecule as a
biomarker of therapy resistance. However, transcriptional profiles connected to its expression in therapy
resistance still remain to be determined.
PB  - Beograd: Srpsko društvo istraživača raka
C3  - Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event
T1  - Analysis of alpha-1 antitrypsin expression in multidrug resistant cell lines
SP  - 48
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5713
ER  - 

@conference{
author = "Ljujić, Mila and Divac Rankov, Aleksandra and Dragoj, Miodrag and Jovanović Stojanov, Sofija",
year = "2021",
abstract = "Identification of the signature molecular factors and transcriptional profiles involved in
therapy resistance is of vital importance in developing new strategies for treatments and disease
monitoring. Tumour secretome is a set of macromolecules secreted by tumour cells into the extracellular
space as a response to changes in tumour environment that at the same time shapes the microenvironment
further promoting specific phenotypes and contributing to cellular plasticity in tumour. Protein alpha-1
antitrypsin (AAT, encoded by SERPINA1 gene) is an acute phase protein that has emerged as one of the key
components in tumour secretome involved in crucial stages of tumour development and progression, with
recent data also implicating it in therapeutic resistance. However, what exactly leads to SERPINA1
upregulation during development of therapy resistance, as well as its biological significance in this process,
is still unclear. Our aim was to analyse SERPINA1 expression in multidrug resistant cell lines and 3D cellular
models. Expression of IL-6 was also analysed, as AAT is an acute phase reactant and its levels increase in
response to inflammatory cytokines. Patients and methods: We analysed SERPINA1 and IL-6 expression in
three different cell lines - human glioblastoma U87, non-small cell lung carcinoma NCI-H460 and colorectal
carcinoma DLD1 as well as their multidrug resistant counterparts U87-TxR, NCI-H460/R and DLD1-TxR,
respectively. In addition, expression analysis was performed in long-term 3D glioblastoma model of U87
cells cultured in alginate microfibers, and compared to long-term 2D cell culture of U87. Quantitative RTPCR was performed using Taqman gene expression assays and data were normalized to GAPDH. Results:
We found that SERPINA1 expression is significantly upregulated in all the multidrug resistant cell lines
analysed compared to their sensitive counterparts. Expression of IL-6 was significantly upregulated in U87-
TxR and DLD1-TxR compared to their parental lines, however NCI-H460/R cell line had lower IL-6 expression
compared to NCI-H460. In 3D glioblastoma model of U87 cells, previously found to exhibit increased
therapy resistance compared to 2D cell culture, both SERPINA1 and IL-6 expression were significantly
upregulated. Conclusion: Our results indicate that SERPINA1 expression correlates with therapy resistance
in analysed cell lines and 3D model of glioblastoma, revealing the potential of utilizing this molecule as a
biomarker of therapy resistance. However, transcriptional profiles connected to its expression in therapy
resistance still remain to be determined.",
publisher = "Beograd: Srpsko društvo istraživača raka",
journal = "Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event",
title = "Analysis of alpha-1 antitrypsin expression in multidrug resistant cell lines",
pages = "48",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5713"
}

Ljujić, M., Divac Rankov, A., Dragoj, M.,& Jovanović Stojanov, S.. (2021). Analysis of alpha-1 antitrypsin expression in multidrug resistant cell lines. in Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event
Beograd: Srpsko društvo istraživača raka., 48.
https://hdl.handle.net/21.15107/rcub_ibiss_5713

Ljujić M, Divac Rankov A, Dragoj M, Jovanović Stojanov S. Analysis of alpha-1 antitrypsin expression in multidrug resistant cell lines. in Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event. 2021;:48.
https://hdl.handle.net/21.15107/rcub_ibiss_5713 .

Ljujić, Mila, Divac Rankov, Aleksandra, Dragoj, Miodrag, Jovanović Stojanov, Sofija, "Analysis of alpha-1 antitrypsin expression in multidrug resistant cell lines" in Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event (2021):48,
https://hdl.handle.net/21.15107/rcub_ibiss_5713 .

TY  - CONF
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Nešović, Marija
AU  - Stepanović, Ana
AU  - Divac Rankov, Aleksandra
AU  - Dragoj, Miodrag
AU  - Nikolić, Igor
AU  - Tasić, Goran
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/123456789/5625
AB  - Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Main characteristics of GBM include high
proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. GBM have high expression of c-Src
tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. Thus,
c-Src emerged as a potential target for GBM therapy. Anticancer properties of c-Src tyrosine kinase inhibitors Si306 and its
prodrug pro-Si306, pyrazolo[3,4-d]pyrimidines were assessed in human GBM cell line U87, its multidrug resistant (MDR)
counterpart U87-TxR, and human primary GBM culture. Si306 and pro-Si306 triggered ROS generation and DNA damage
in sensitive and MDR GBM cell lines, as well as primary GBM cells. Both compounds induced a prominent cell death in
primary GBM culture, while the effect on GBM cell lines was predominantly antiproliferative, characterized by decrease in
Ki-67 expression and cell cycle disturbance. Moreover, the investigated compounds made primary GBM culture more prone
to anoikis. In addition, Si306 and pro-Si306 showed strong antiproliferative effect in U87 xenografts in zebrafish embryo
model. The antiglioblastoma effects of investigated c-Src inhibitors were more prominent when compared to dasatinib, a
well-known tyrosine kinase inhibitor. The presence of the MDR phenotype did not diminish the activity of the compounds.
The investigated pyrazolo[3,4-d]pyrimidines displayed significant anticancer potential in GBM which makes them good
candidates for further development regarding treatment of this cancer type.
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  - Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma
SP  - 35
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5625
ER  - 

@conference{
author = "Dinić, Jelena and Podolski-Renić, Ana and Nešović, Marija and Stepanović, Ana and Divac Rankov, Aleksandra and Dragoj, Miodrag and Nikolić, Igor and Tasić, Goran and Pešić, Milica",
year = "2020",
abstract = "Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Main characteristics of GBM include high
proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. GBM have high expression of c-Src
tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. Thus,
c-Src emerged as a potential target for GBM therapy. Anticancer properties of c-Src tyrosine kinase inhibitors Si306 and its
prodrug pro-Si306, pyrazolo[3,4-d]pyrimidines were assessed in human GBM cell line U87, its multidrug resistant (MDR)
counterpart U87-TxR, and human primary GBM culture. Si306 and pro-Si306 triggered ROS generation and DNA damage
in sensitive and MDR GBM cell lines, as well as primary GBM cells. Both compounds induced a prominent cell death in
primary GBM culture, while the effect on GBM cell lines was predominantly antiproliferative, characterized by decrease in
Ki-67 expression and cell cycle disturbance. Moreover, the investigated compounds made primary GBM culture more prone
to anoikis. In addition, Si306 and pro-Si306 showed strong antiproliferative effect in U87 xenografts in zebrafish embryo
model. The antiglioblastoma effects of investigated c-Src inhibitors were more prominent when compared to dasatinib, a
well-known tyrosine kinase inhibitor. The presence of the MDR phenotype did not diminish the activity of the compounds.
The investigated pyrazolo[3,4-d]pyrimidines displayed significant anticancer potential in GBM which makes them good
candidates for further development regarding treatment of this cancer type.",
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 = "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma",
pages = "35",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5625"
}

Dinić, J., Podolski-Renić, A., Nešović, M., Stepanović, A., Divac Rankov, A., Dragoj, M., Nikolić, I., Tasić, G.,& Pešić, M.. (2020). Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma. 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., 35.
https://hdl.handle.net/21.15107/rcub_ibiss_5625

Dinić J, Podolski-Renić A, Nešović M, Stepanović A, Divac Rankov A, Dragoj M, Nikolić I, Tasić G, Pešić M. Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma. 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;:35.
https://hdl.handle.net/21.15107/rcub_ibiss_5625 .

Dinić, Jelena, Podolski-Renić, Ana, Nešović, Marija, Stepanović, Ana, Divac Rankov, Aleksandra, Dragoj, Miodrag, Nikolić, Igor, Tasić, Goran, Pešić, Milica, "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma" 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):35,
https://hdl.handle.net/21.15107/rcub_ibiss_5625 .

TY  - CHAP
AU  - Kračun-Kolarević, Margareta
AU  - Kolarević, Stoimir
AU  - Jovanović, Jovana
AU  - Đorđević, Jelena
AU  - Ilić, Marija
AU  - Sunjog, Karolina
AU  - Kostić-Vuković, Jovana
AU  - Divac Rankov, Aleksandra
AU  - Ilić, Bojan
AU  - Pešić, Vladimir
AU  - Vuković-Gačić, Branka
AU  - Paunović, Momir
PY  - 2020
UR  - https://link.springer.com/chapter/10.1007/698_2019_425
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3951
AB  - Montenegrin surface water and groundwater are important for the Balkan Peninsula since they are connected by the transboundary Dinaric Karst Aquifer System with the waters of additional five countries. The pollution from the surface water can rapidly infiltrate in aquifer and endanger this sensible ecosystem and the health of humans through drinking water supply. This chapter gives insights in the pressures of pollution on Montenegrin waters and in a limited literature data regarding freshwater ecotoxicological studies in Montenegro. Also, this chapter provides new ecotoxicological data obtained during survey in 2019, with a focus on the sites which are identified as hotspots of fecal pollution. The highest responses of biomarkers which indicate embryotoxic, genotoxic, and phytotoxic effects in zebrafish embryo test and in roots of Allium cepa were obtained at Ćehotina – downstream of Pljevlja. Similar results were detected at the site downstream Mojkovac at Tara, yet this site is affected by different type of pollution. Genotoxic endpoints in zebrafish stressed out sites on Morača and Lim rivers which are under pressures of fecal pollution. The data in this chapter provides an insight into current status obtained by the ex situ bioassays and indicates need for more comprehensive in situ assessment.
PB  - Springer
T2  - The Rivers of Montenegro
T1  - Impact of Pollution on Rivers in Montenegro: Ecotoxicological Perspective
DO  - 10.1007/698_2019_425
SP  - 111
EP  - 133
ER  - 

@inbook{
editor = "Pešić, Vladimir, Paunović, Momir, Kostianoy, Andrey G.",
author = "Kračun-Kolarević, Margareta and Kolarević, Stoimir and Jovanović, Jovana and Đorđević, Jelena and Ilić, Marija and Sunjog, Karolina and Kostić-Vuković, Jovana and Divac Rankov, Aleksandra and Ilić, Bojan and Pešić, Vladimir and Vuković-Gačić, Branka and Paunović, Momir",
year = "2020",
abstract = "Montenegrin surface water and groundwater are important for the Balkan Peninsula since they are connected by the transboundary Dinaric Karst Aquifer System with the waters of additional five countries. The pollution from the surface water can rapidly infiltrate in aquifer and endanger this sensible ecosystem and the health of humans through drinking water supply. This chapter gives insights in the pressures of pollution on Montenegrin waters and in a limited literature data regarding freshwater ecotoxicological studies in Montenegro. Also, this chapter provides new ecotoxicological data obtained during survey in 2019, with a focus on the sites which are identified as hotspots of fecal pollution. The highest responses of biomarkers which indicate embryotoxic, genotoxic, and phytotoxic effects in zebrafish embryo test and in roots of Allium cepa were obtained at Ćehotina – downstream of Pljevlja. Similar results were detected at the site downstream Mojkovac at Tara, yet this site is affected by different type of pollution. Genotoxic endpoints in zebrafish stressed out sites on Morača and Lim rivers which are under pressures of fecal pollution. The data in this chapter provides an insight into current status obtained by the ex situ bioassays and indicates need for more comprehensive in situ assessment.",
publisher = "Springer",
journal = "The Rivers of Montenegro",
booktitle = "Impact of Pollution on Rivers in Montenegro: Ecotoxicological Perspective",
doi = "10.1007/698_2019_425",
pages = "111-133"
}

Pešić, V., Paunović, M., Kostianoy, A. G., Kračun-Kolarević, M., Kolarević, S., Jovanović, J., Đorđević, J., Ilić, M., Sunjog, K., Kostić-Vuković, J., Divac Rankov, A., Ilić, B., Pešić, V., Vuković-Gačić, B.,& Paunović, M.. (2020). Impact of Pollution on Rivers in Montenegro: Ecotoxicological Perspective. in The Rivers of Montenegro
Springer., 111-133.
https://doi.org/10.1007/698_2019_425

Pešić V, Paunović M, Kostianoy AG, Kračun-Kolarević M, Kolarević S, Jovanović J, Đorđević J, Ilić M, Sunjog K, Kostić-Vuković J, Divac Rankov A, Ilić B, Pešić V, Vuković-Gačić B, Paunović M. Impact of Pollution on Rivers in Montenegro: Ecotoxicological Perspective. in The Rivers of Montenegro. 2020;:111-133.
doi:10.1007/698_2019_425 .

Pešić, Vladimir, Paunović, Momir, Kostianoy, Andrey G., Kračun-Kolarević, Margareta, Kolarević, Stoimir, Jovanović, Jovana, Đorđević, Jelena, Ilić, Marija, Sunjog, Karolina, Kostić-Vuković, Jovana, Divac Rankov, Aleksandra, Ilić, Bojan, Pešić, Vladimir, Vuković-Gačić, Branka, Paunović, Momir, "Impact of Pollution on Rivers in Montenegro: Ecotoxicological Perspective" in The Rivers of Montenegro (2020):111-133,
https://doi.org/10.1007/698_2019_425 . .

TY  - JOUR
AU  - Nešović, Marija
AU  - Divac Rankov, Aleksandra
AU  - Podolski-Renić, Ana
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Mancini, Arianna
AU  - Schenone, Silvia
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2020
UR  - https://www.mdpi.com/2072-6694/12/6/1570
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3818
AB  - Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.
PB  - Basel : MDPI
T2  - Cancers (Basel)
T1  - Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo
IS  - 6
VL  - 12
DO  - 10.3390/cancers12061570
SP  - 1570
ER  - 

@article{
author = "Nešović, Marija and Divac Rankov, Aleksandra and Podolski-Renić, Ana and Nikolić, Igor and Tasić, Goran and Mancini, Arianna and Schenone, Silvia and Pešić, Milica and Dinić, Jelena",
year = "2020",
abstract = "Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.",
publisher = "Basel : MDPI",
journal = "Cancers (Basel)",
title = "Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo",
number = "6",
volume = "12",
doi = "10.3390/cancers12061570",
pages = "1570"
}

Nešović, M., Divac Rankov, A., Podolski-Renić, A., Nikolić, I., Tasić, G., Mancini, A., Schenone, S., Pešić, M.,& Dinić, J.. (2020). Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo. in Cancers (Basel)
Basel : MDPI., 12(6), 1570.
https://doi.org/10.3390/cancers12061570

Nešović M, Divac Rankov A, Podolski-Renić A, Nikolić I, Tasić G, Mancini A, Schenone S, Pešić M, Dinić J. Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo. in Cancers (Basel). 2020;12(6):1570.
doi:10.3390/cancers12061570 .

Nešović, Marija, Divac Rankov, Aleksandra, Podolski-Renić, Ana, Nikolić, Igor, Tasić, Goran, Mancini, Arianna, Schenone, Silvia, Pešić, Milica, Dinić, Jelena, "Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo" in Cancers (Basel), 12, no. 6 (2020):1570,
https://doi.org/10.3390/cancers12061570 . .

TY  - CONF
AU  - Nešović, Marija
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Divac Rankov, Aleksandra
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Botta, Maurizio
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6048
AB  - Background: Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO
grade IV) brain tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in
survival, migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for
GBM therapy. Materials and methods: Antiproliferative effect of c-Src inhibitors pyrozolo[3,4-d]
pyrimidines, Si306 and its prodrug pro-Si306, was assessed in human GBM cell line U87, multidrug
resistant (MDR) U87-TxR, and primary GBM cells by MTT assay. Anti-migratory and anti-invasive
effects of c-Src inhibitors were evaluated by gelatin degradation and transwell invasion assays.
Their effect on c-Src, extracellular signal-related kinase (ERK), and focal adhesion kinase (FAK)
expression was analyzed by western-blot and flow-cytometry. Zebrafish model was used to
evaluate anti-invasive potential of pro-Si306 in U87 xenografts in vivo. Results and conclusions:
c-Src inhibitors were more efficient in cell growth inhibition compared to dasatinib, a well-known tyrosine kinase inhibitor. The potency of Si306 and pro-Si306 was not affected by the
MDR phenotype. Migratory potential of U87, U87-TxR, and primary GBM cells was significantly
decreased by both inhibitors. Si306 and pro-Si306 also compromised cells’ ability to degrade the
matrix and invade through basement membrane. Both compounds reduced phosporylation of
c-Src, and its downstream signaling components, ERK and FAK, in GBM cell lines. In vivo, pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish model. Considering their
ability to suppress migration and invasion and overcome MDR, Si306 and pro-Si306 could be
considered in GBM treatment alone or in combination with other chemotherapeutics.
PB  - Belgrade: Serbian Association for Cancer Research
C3  - Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia
T1  - c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma
SP  - 46
EP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6048
ER  - 

@conference{
author = "Nešović, Marija and Podolski-Renić, Ana and Stanković, Tijana and Divac Rankov, Aleksandra and Nikolić, Igor and Tasić, Goran and Botta, Maurizio and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Background: Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO
grade IV) brain tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in
survival, migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for
GBM therapy. Materials and methods: Antiproliferative effect of c-Src inhibitors pyrozolo[3,4-d]
pyrimidines, Si306 and its prodrug pro-Si306, was assessed in human GBM cell line U87, multidrug
resistant (MDR) U87-TxR, and primary GBM cells by MTT assay. Anti-migratory and anti-invasive
effects of c-Src inhibitors were evaluated by gelatin degradation and transwell invasion assays.
Their effect on c-Src, extracellular signal-related kinase (ERK), and focal adhesion kinase (FAK)
expression was analyzed by western-blot and flow-cytometry. Zebrafish model was used to
evaluate anti-invasive potential of pro-Si306 in U87 xenografts in vivo. Results and conclusions:
c-Src inhibitors were more efficient in cell growth inhibition compared to dasatinib, a well-known tyrosine kinase inhibitor. The potency of Si306 and pro-Si306 was not affected by the
MDR phenotype. Migratory potential of U87, U87-TxR, and primary GBM cells was significantly
decreased by both inhibitors. Si306 and pro-Si306 also compromised cells’ ability to degrade the
matrix and invade through basement membrane. Both compounds reduced phosporylation of
c-Src, and its downstream signaling components, ERK and FAK, in GBM cell lines. In vivo, pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish model. Considering their
ability to suppress migration and invasion and overcome MDR, Si306 and pro-Si306 could be
considered in GBM treatment alone or in combination with other chemotherapeutics.",
publisher = "Belgrade: Serbian Association for Cancer Research",
journal = "Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia",
title = "c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma",
pages = "46-46",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6048"
}

Nešović, M., Podolski-Renić, A., Stanković, T., Divac Rankov, A., Nikolić, I., Tasić, G., Botta, M., Pešić, M.,& Dinić, J.. (2019). c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma. in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia
Belgrade: Serbian Association for Cancer Research., 46-46.
https://hdl.handle.net/21.15107/rcub_ibiss_6048

Nešović M, Podolski-Renić A, Stanković T, Divac Rankov A, Nikolić I, Tasić G, Botta M, Pešić M, Dinić J. c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma. in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia. 2019;:46-46.
https://hdl.handle.net/21.15107/rcub_ibiss_6048 .

Nešović, Marija, Podolski-Renić, Ana, Stanković, Tijana, Divac Rankov, Aleksandra, Nikolić, Igor, Tasić, Goran, Botta, Maurizio, Pešić, Milica, Dinić, Jelena, "c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma" in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia (2019):46-46,
https://hdl.handle.net/21.15107/rcub_ibiss_6048 .

TY  - CONF
AU  - Dinić, Jelena
AU  - Nešović, Marija
AU  - Divac Rankov, Aleksandra
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Lazić, Katarina
AU  - Dimas, Kostas
AU  - Botta, Maurizio
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6042
AB  - Zebrafish (Danio rerio) is an excellent model for studying toxicity and biological activities of novel compounds with anticancer potential. This model is widely utilized in biological research as it is comparable to human counterpart both molecularly and pathologically. As an in vivo system for toxicology, zebrafish has numerous advantages such as rapid and ex utero development, transparent embryos in early stages, high fecundity allowing high-throughput screening and cost effectiveness. Furthermore, evaluation of known toxic compounds in zebrafish revealed 63–100% predictability making zebrafish a very useful tool for studying toxic effects [1, 2]. In addition, embryonic zebrafish cancer models can be used for studying pathways and processes relevant to human malignancy including tumor-induced angiogenesis, tumor invasiveness, proliferation and migration. These models can be generated using transgenesis, gene inactivation, xenotransplantation, and cancerogenic induction. Herein, we present the results obtained in zebrafish toxicity studies of siramesine, a sigma receptor agonist with anticancer potential. Concentration dependent increase in lethality, induced by siramesine treatment, was observed in zebrafish embryos at 24 h post fertilization (hpf), 48 hpf and 72 hpf. Various concentration dependent toxic effects on embryo development were also observed, as well as decreased hatching rate in embryos treated with 5 µM and 10 µM siramesine at 72 hpf. Results obtained in zebrafish cancer model generated via xenotransplantation are also presented. This model was utilized to study the effect of Src tyrosine kinase inhibitor pro-LDS10 on the invasiveness of microinjected human glioblastoma cell line U87. Treatment with 5 µM pro-LDS10 resulted in significant reduction of U87 migratory potential at 4 days post injection.
PB  - COST Action CA17104
C3  - Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
T1  - Evaluation of anticancer compounds activity and toxicity in zebrafish model
SP  - 34
EP  - 34
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6042
ER  - 

@conference{
author = "Dinić, Jelena and Nešović, Marija and Divac Rankov, Aleksandra and Podolski-Renić, Ana and Stanković, Tijana and Dragoj, Miodrag and Jovanović, Mirna and Lazić, Katarina and Dimas, Kostas and Botta, Maurizio and Pešić, Milica",
year = "2019",
abstract = "Zebrafish (Danio rerio) is an excellent model for studying toxicity and biological activities of novel compounds with anticancer potential. This model is widely utilized in biological research as it is comparable to human counterpart both molecularly and pathologically. As an in vivo system for toxicology, zebrafish has numerous advantages such as rapid and ex utero development, transparent embryos in early stages, high fecundity allowing high-throughput screening and cost effectiveness. Furthermore, evaluation of known toxic compounds in zebrafish revealed 63–100% predictability making zebrafish a very useful tool for studying toxic effects [1, 2]. In addition, embryonic zebrafish cancer models can be used for studying pathways and processes relevant to human malignancy including tumor-induced angiogenesis, tumor invasiveness, proliferation and migration. These models can be generated using transgenesis, gene inactivation, xenotransplantation, and cancerogenic induction. Herein, we present the results obtained in zebrafish toxicity studies of siramesine, a sigma receptor agonist with anticancer potential. Concentration dependent increase in lethality, induced by siramesine treatment, was observed in zebrafish embryos at 24 h post fertilization (hpf), 48 hpf and 72 hpf. Various concentration dependent toxic effects on embryo development were also observed, as well as decreased hatching rate in embryos treated with 5 µM and 10 µM siramesine at 72 hpf. Results obtained in zebrafish cancer model generated via xenotransplantation are also presented. This model was utilized to study the effect of Src tyrosine kinase inhibitor pro-LDS10 on the invasiveness of microinjected human glioblastoma cell line U87. Treatment with 5 µM pro-LDS10 resulted in significant reduction of U87 migratory potential at 4 days post injection.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy",
title = "Evaluation of anticancer compounds activity and toxicity in zebrafish model",
pages = "34-34",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6042"
}

Dinić, J., Nešović, M., Divac Rankov, A., Podolski-Renić, A., Stanković, T., Dragoj, M., Jovanović, M., Lazić, K., Dimas, K., Botta, M.,& Pešić, M.. (2019). Evaluation of anticancer compounds activity and toxicity in zebrafish model. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
COST Action CA17104., 34-34.
https://hdl.handle.net/21.15107/rcub_ibiss_6042

Dinić J, Nešović M, Divac Rankov A, Podolski-Renić A, Stanković T, Dragoj M, Jovanović M, Lazić K, Dimas K, Botta M, Pešić M. Evaluation of anticancer compounds activity and toxicity in zebrafish model. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy. 2019;:34-34.
https://hdl.handle.net/21.15107/rcub_ibiss_6042 .

Dinić, Jelena, Nešović, Marija, Divac Rankov, Aleksandra, Podolski-Renić, Ana, Stanković, Tijana, Dragoj, Miodrag, Jovanović, Mirna, Lazić, Katarina, Dimas, Kostas, Botta, Maurizio, Pešić, Milica, "Evaluation of anticancer compounds activity and toxicity in zebrafish model" in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy (2019):34-34,
https://hdl.handle.net/21.15107/rcub_ibiss_6042 .

TY  - CONF
AU  - Nešović, Marija
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Divac Rankov, Aleksandra
AU  - Fallacara, Anna Lucia
AU  - Schenone, Silvia
AU  - Botta, Maurizio
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6045
AB  - Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO grade IV) brain
tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in survival,
migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for GBM
therapy. Cytotoxicity of c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306,
was investigated in human GBM cell line U87 and its multidrug resistant (MDR) counterpart
U87-TxR by MTT assay. Anti-migratory and anti-invasive effects of Si306 and pro-Si306 were
assessed by wound healing, gelatin degradation and transwell invasion assays. The effect of cSrc inhibitors on P-glycoprotein (P-gp) activity in U87-TxR cells was analyzed by flow cytometry. Their ability to reverse paclitaxel resistance in MDR cells was also assessed. Zebrafish model was used to evaluate anti-invasive potential of pro-Si306 on U87 xenografts in vivo. Novel c-Src inhibitors were significantly more efficient in cell growth inhibition compared to the well-known tyrosine kinase inhibitor dasatinib. The efficacy of Si306 and pro-Si306 was not affected by the MDR phenotype.
Migratory potential of U87 and U87-TxR cells was significantly decreased by both inhibitors.
The ability of cells to degrade the matrix and invade through basement membrane was also
significantly impaired upon treatment with Si306 and its prodrug. Assessment of intracellular
accumulation of fluorescent P-gp substrate showed that both compounds inhibited P-gp activity
in U87-TxR cells. Si306 and pro-Si306 also enhanced the paclitaxel efficacy in resistant
glioblastoma. In vivo pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish
model. Considering their ability to suppress migration and invasion and overcome MDR, Si306 and proSi306 could be considered in GBM treatment alone or in combination with other
chemotherapeutics.
PB  - COST Action CM1407
C3  - COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium
T1  - The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma
SP  - 9
EP  - 9
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6045
ER  - 

@conference{
author = "Nešović, Marija and Podolski-Renić, Ana and Stanković, Tijana and Divac Rankov, Aleksandra and Fallacara, Anna Lucia and Schenone, Silvia and Botta, Maurizio and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO grade IV) brain
tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in survival,
migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for GBM
therapy. Cytotoxicity of c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306,
was investigated in human GBM cell line U87 and its multidrug resistant (MDR) counterpart
U87-TxR by MTT assay. Anti-migratory and anti-invasive effects of Si306 and pro-Si306 were
assessed by wound healing, gelatin degradation and transwell invasion assays. The effect of cSrc inhibitors on P-glycoprotein (P-gp) activity in U87-TxR cells was analyzed by flow cytometry. Their ability to reverse paclitaxel resistance in MDR cells was also assessed. Zebrafish model was used to evaluate anti-invasive potential of pro-Si306 on U87 xenografts in vivo. Novel c-Src inhibitors were significantly more efficient in cell growth inhibition compared to the well-known tyrosine kinase inhibitor dasatinib. The efficacy of Si306 and pro-Si306 was not affected by the MDR phenotype.
Migratory potential of U87 and U87-TxR cells was significantly decreased by both inhibitors.
The ability of cells to degrade the matrix and invade through basement membrane was also
significantly impaired upon treatment with Si306 and its prodrug. Assessment of intracellular
accumulation of fluorescent P-gp substrate showed that both compounds inhibited P-gp activity
in U87-TxR cells. Si306 and pro-Si306 also enhanced the paclitaxel efficacy in resistant
glioblastoma. In vivo pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish
model. Considering their ability to suppress migration and invasion and overcome MDR, Si306 and proSi306 could be considered in GBM treatment alone or in combination with other
chemotherapeutics.",
publisher = "COST Action CM1407",
journal = "COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium",
title = "The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma",
pages = "9-9",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6045"
}

Nešović, M., Podolski-Renić, A., Stanković, T., Divac Rankov, A., Fallacara, A. L., Schenone, S., Botta, M., Pešić, M.,& Dinić, J.. (2019). The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma. in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium
COST Action CM1407., 9-9.
https://hdl.handle.net/21.15107/rcub_ibiss_6045

Nešović M, Podolski-Renić A, Stanković T, Divac Rankov A, Fallacara AL, Schenone S, Botta M, Pešić M, Dinić J. The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma. in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium. 2019;:9-9.
https://hdl.handle.net/21.15107/rcub_ibiss_6045 .

Nešović, Marija, Podolski-Renić, Ana, Stanković, Tijana, Divac Rankov, Aleksandra, Fallacara, Anna Lucia, Schenone, Silvia, Botta, Maurizio, Pešić, Milica, Dinić, Jelena, "The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma" in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium (2019):9-9,
https://hdl.handle.net/21.15107/rcub_ibiss_6045 .

TY  - JOUR
AU  - Nestorović Živković, Jasmina
AU  - Živković, Suzana
AU  - Šiler, Branislav
AU  - Aničić, Neda
AU  - Dmitrović, Slavica
AU  - Divac-Rankov, Aleksandra
AU  - Giba, Zlatko
AU  - Mišić, Danijela
PY  - 2018
UR  - http://www.doiserbia.nb.rs/Article.aspx?ID=0354-46641700026N
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3017
UR  - http://www.serbiosoc.org.rs/arch/index.php/abs/article/view/1881
AB  - Methanol extracts of three endemic Nepeta species were analyzed for their main secondary metabolites, terpenes and phenolics, and further investigated for antioxidant capacity and embryonic toxicity in zebrafish. UHPLC/DAD/(±) HESI-MS/MS analysis showed that the dominant compound in N. rtanjensis was trans,cis-nepetalactone, the cis,trans isomer of this monoterpene lactone was dominant in N. sibirica, while nepetalactone was detected only in traces in N. nervosa. In all investigated species, rosmarinic acid was the dominant phenolic compound, while other identified phenolic acids (chlorogenic, neochlorogenic and caffeic) were present in considerably lower amounts. ABTS and DPPH assays showed that the methanol extracts of N. rtanjensis, N. sibirica and especially N. nervosa possessed strong antioxidant activities, with the FRAP assay revealing high ferric-reducing abilities for all three tested species. Such a strong antioxidant potential, especially as manifested in the DPPH and FRAP assays, can be attributed to phenolic acids, and in the first place to rosmarinic acid. Increased lethality of zebrafish embryos in any of the treatments was not observed, but several toxic effects on embryonic development were recorded, such as pericardial and yolk sac edema. As in other Nepeta species, the three studied endemic species possessed a great potential for food conservation or as medicinal supplements if applied in optimized concentrations; however, alternative sources of plant material (e.g. field cultivation) should be established bearing in mind their vulnerability in nature.
T2  - Archives of Biological Sciences
T2  - Archives of Biological Sciences
T1  - Differences in bioactivity of three endemic Nepeta species arising from main terpenoid and phenolic constituents
IS  - 1
VL  - 70
DO  - 10.2298/ABS170616026N
SP  - 63
EP  - 76
ER  - 

@article{
author = "Nestorović Živković, Jasmina and Živković, Suzana and Šiler, Branislav and Aničić, Neda and Dmitrović, Slavica and Divac-Rankov, Aleksandra and Giba, Zlatko and Mišić, Danijela",
year = "2018",
abstract = "Methanol extracts of three endemic Nepeta species were analyzed for their main secondary metabolites, terpenes and phenolics, and further investigated for antioxidant capacity and embryonic toxicity in zebrafish. UHPLC/DAD/(±) HESI-MS/MS analysis showed that the dominant compound in N. rtanjensis was trans,cis-nepetalactone, the cis,trans isomer of this monoterpene lactone was dominant in N. sibirica, while nepetalactone was detected only in traces in N. nervosa. In all investigated species, rosmarinic acid was the dominant phenolic compound, while other identified phenolic acids (chlorogenic, neochlorogenic and caffeic) were present in considerably lower amounts. ABTS and DPPH assays showed that the methanol extracts of N. rtanjensis, N. sibirica and especially N. nervosa possessed strong antioxidant activities, with the FRAP assay revealing high ferric-reducing abilities for all three tested species. Such a strong antioxidant potential, especially as manifested in the DPPH and FRAP assays, can be attributed to phenolic acids, and in the first place to rosmarinic acid. Increased lethality of zebrafish embryos in any of the treatments was not observed, but several toxic effects on embryonic development were recorded, such as pericardial and yolk sac edema. As in other Nepeta species, the three studied endemic species possessed a great potential for food conservation or as medicinal supplements if applied in optimized concentrations; however, alternative sources of plant material (e.g. field cultivation) should be established bearing in mind their vulnerability in nature.",
journal = "Archives of Biological Sciences, Archives of Biological Sciences",
title = "Differences in bioactivity of three endemic Nepeta species arising from main terpenoid and phenolic constituents",
number = "1",
volume = "70",
doi = "10.2298/ABS170616026N",
pages = "63-76"
}

Nestorović Živković, J., Živković, S., Šiler, B., Aničić, N., Dmitrović, S., Divac-Rankov, A., Giba, Z.,& Mišić, D.. (2018). Differences in bioactivity of three endemic Nepeta species arising from main terpenoid and phenolic constituents. in Archives of Biological Sciences, 70(1), 63-76.
https://doi.org/10.2298/ABS170616026N

Nestorović Živković J, Živković S, Šiler B, Aničić N, Dmitrović S, Divac-Rankov A, Giba Z, Mišić D. Differences in bioactivity of three endemic Nepeta species arising from main terpenoid and phenolic constituents. in Archives of Biological Sciences. 2018;70(1):63-76.
doi:10.2298/ABS170616026N .

Nestorović Živković, Jasmina, Živković, Suzana, Šiler, Branislav, Aničić, Neda, Dmitrović, Slavica, Divac-Rankov, Aleksandra, Giba, Zlatko, Mišić, Danijela, "Differences in bioactivity of three endemic Nepeta species arising from main terpenoid and phenolic constituents" in Archives of Biological Sciences, 70, no. 1 (2018):63-76,
https://doi.org/10.2298/ABS170616026N . .

TY  - JOUR
AU  - Babić, Tamara
AU  - Dinić, Jelena
AU  - Stojković Burić, Sonja
AU  - Hadzic, Stefan
AU  - Pešić, Milica
AU  - Radojković, Dragica
AU  - Divac Rankov, Aleksandra
PY  - 2018
UR  - https://akjournals.com/view/journals/018/69/4/article-p395.xml
UR  - https://radar.ibiss.bg.ac.rs/123456789/3881
AB  - Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.
PB  - Budapest : Akadémiai Kiadó
T2  - Acta Biologica Hungarica
T1  - Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models
IS  - 4
VL  - 69
DO  - 10.1556/018.69.2018.4.3
SP  - 395
EP  - 410
ER  - 

@article{
author = "Babić, Tamara and Dinić, Jelena and Stojković Burić, Sonja and Hadzic, Stefan and Pešić, Milica and Radojković, Dragica and Divac Rankov, Aleksandra",
year = "2018",
abstract = "Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.",
publisher = "Budapest : Akadémiai Kiadó",
journal = "Acta Biologica Hungarica",
title = "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models",
number = "4",
volume = "69",
doi = "10.1556/018.69.2018.4.3",
pages = "395-410"
}

Babić, T., Dinić, J., Stojković Burić, S., Hadzic, S., Pešić, M., Radojković, D.,& Divac Rankov, A.. (2018). Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models. in Acta Biologica Hungarica
Budapest : Akadémiai Kiadó., 69(4), 395-410.
https://doi.org/10.1556/018.69.2018.4.3

Babić T, Dinić J, Stojković Burić S, Hadzic S, Pešić M, Radojković D, Divac Rankov A. Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models. in Acta Biologica Hungarica. 2018;69(4):395-410.
doi:10.1556/018.69.2018.4.3 .

Babić, Tamara, Dinić, Jelena, Stojković Burić, Sonja, Hadzic, Stefan, Pešić, Milica, Radojković, Dragica, Divac Rankov, Aleksandra, "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models" in Acta Biologica Hungarica, 69, no. 4 (2018):395-410,
https://doi.org/10.1556/018.69.2018.4.3 . .

TY  - JOUR
AU  - Babić, Tamara
AU  - Dinić, Jelena
AU  - Stojković Burić, Sonja
AU  - Hadžić, Stefan
AU  - Pešić, Milica
AU  - Radojković, Dragica
AU  - Divac Rankov, Aleksandra
PY  - 2018
UR  - https://www.akademiai.com/doi/10.1556/018.69.2018.4.3
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3231
AB  - Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.
T2  - Acta Biologica Hungarica
T1  - Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models.
IS  - 4
VL  - 69
DO  - 10.1556/018.69.2018.4.3
SP  - 395
EP  - 410
ER  - 

@article{
author = "Babić, Tamara and Dinić, Jelena and Stojković Burić, Sonja and Hadžić, Stefan and Pešić, Milica and Radojković, Dragica and Divac Rankov, Aleksandra",
year = "2018",
abstract = "Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.",
journal = "Acta Biologica Hungarica",
title = "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models.",
number = "4",
volume = "69",
doi = "10.1556/018.69.2018.4.3",
pages = "395-410"
}

Babić, T., Dinić, J., Stojković Burić, S., Hadžić, S., Pešić, M., Radojković, D.,& Divac Rankov, A.. (2018). Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models.. in Acta Biologica Hungarica, 69(4), 395-410.
https://doi.org/10.1556/018.69.2018.4.3

Babić T, Dinić J, Stojković Burić S, Hadžić S, Pešić M, Radojković D, Divac Rankov A. Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models.. in Acta Biologica Hungarica. 2018;69(4):395-410.
doi:10.1556/018.69.2018.4.3 .

Babić, Tamara, Dinić, Jelena, Stojković Burić, Sonja, Hadžić, Stefan, Pešić, Milica, Radojković, Dragica, Divac Rankov, Aleksandra, "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models." in Acta Biologica Hungarica, 69, no. 4 (2018):395-410,
https://doi.org/10.1556/018.69.2018.4.3 . .

TY  - GEN
AU  - Divac Rankov, Aleksandra
AU  - Ljujić, Mila
AU  - Petrić, Marija
AU  - Radojković, Dragica
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2017
UR  - http://link.springer.com/10.1007/s00418-017-1590-4
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2796
AB  - Autophagy is linked to multiple cancer-related signaling pathways, and represents a defense mechanism for cancer cells under therapeutic stress. The crosstalk between apoptosis and autophagy is essential for both tumorigenesis and embryonic development. We studied the influence of autophagy on cell survival in pro-apoptotic conditions induced by anticancer drugs in three model systems: human cancer cells (NCI-H460, COR-L23 and U87), human normal cells (HaCaT and MRC-5) and zebrafish embryos (Danio rerio). Autophagy induction with AZD2014 and tamoxifen antagonized the pro-apoptotic effect of chemotherapeutics doxorubicin and cisplatin in cell lines, while autophagy inhibition by wortmannin and chloroquine synergized the action of both anticancer agents. This effect was further verified by assessing cleaved caspase-3 and PARP-1 levels. Autophagy inhibitors significantly increased both apoptotic markers when applied in combination with doxorubicin while autophagy inducers had the opposite effect. In a similar manner, autophagy induction in zebrafish embryos prevented cisplatin-induced apoptosis in the tail region while autophagy inhibition increased cell death in the tail and retina of cisplatin-treated animals. Autophagy modulation with direct inhibitors of the PI3kinase/Akt/mTOR pathway (AZD2014 and wortmannin) triggered the cellular response to anticancer drugs more effectively in NCI-H460 and zebrafish embryonic models compared to HaCaT suggesting that these modulators are selective towards rapidly proliferating cells. Therefore, evaluating the autophagic properties of chemotherapeutics could help determine more accurately the fate of different cell types under treatment. Our study underlines the importance of testing autophagic activity of potential anticancer agents in a comparative approach to develop more rational anticancer therapeutic strategies.
T2  - Histochemistry and Cell Biology
T1  - Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells
DO  - 10.1007/s00418-017-1590-4
ER  - 

@misc{
author = "Divac Rankov, Aleksandra and Ljujić, Mila and Petrić, Marija and Radojković, Dragica and Pešić, Milica and Dinić, Jelena",
year = "2017",
abstract = "Autophagy is linked to multiple cancer-related signaling pathways, and represents a defense mechanism for cancer cells under therapeutic stress. The crosstalk between apoptosis and autophagy is essential for both tumorigenesis and embryonic development. We studied the influence of autophagy on cell survival in pro-apoptotic conditions induced by anticancer drugs in three model systems: human cancer cells (NCI-H460, COR-L23 and U87), human normal cells (HaCaT and MRC-5) and zebrafish embryos (Danio rerio). Autophagy induction with AZD2014 and tamoxifen antagonized the pro-apoptotic effect of chemotherapeutics doxorubicin and cisplatin in cell lines, while autophagy inhibition by wortmannin and chloroquine synergized the action of both anticancer agents. This effect was further verified by assessing cleaved caspase-3 and PARP-1 levels. Autophagy inhibitors significantly increased both apoptotic markers when applied in combination with doxorubicin while autophagy inducers had the opposite effect. In a similar manner, autophagy induction in zebrafish embryos prevented cisplatin-induced apoptosis in the tail region while autophagy inhibition increased cell death in the tail and retina of cisplatin-treated animals. Autophagy modulation with direct inhibitors of the PI3kinase/Akt/mTOR pathway (AZD2014 and wortmannin) triggered the cellular response to anticancer drugs more effectively in NCI-H460 and zebrafish embryonic models compared to HaCaT suggesting that these modulators are selective towards rapidly proliferating cells. Therefore, evaluating the autophagic properties of chemotherapeutics could help determine more accurately the fate of different cell types under treatment. Our study underlines the importance of testing autophagic activity of potential anticancer agents in a comparative approach to develop more rational anticancer therapeutic strategies.",
journal = "Histochemistry and Cell Biology",
title = "Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells",
doi = "10.1007/s00418-017-1590-4"
}

Divac Rankov, A., Ljujić, M., Petrić, M., Radojković, D., Pešić, M.,& Dinić, J.. (2017). Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells. in Histochemistry and Cell Biology.
https://doi.org/10.1007/s00418-017-1590-4

Divac Rankov A, Ljujić M, Petrić M, Radojković D, Pešić M, Dinić J. Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells. in Histochemistry and Cell Biology. 2017;.
doi:10.1007/s00418-017-1590-4 .

Divac Rankov, Aleksandra, Ljujić, Mila, Petrić, Marija, Radojković, Dragica, Pešić, Milica, Dinić, Jelena, "Targeting autophagy to modulate cell survival: a comparative analysis in cancer, normal and embryonic cells" in Histochemistry and Cell Biology (2017),
https://doi.org/10.1007/s00418-017-1590-4 . .