TY  - CONF
AU  - Nešović, Marija
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Tsimplouli, Chrisiida
AU  - Sereti, Evangelia
AU  - Dragoj, Miodrag
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Jovanović, Mirna
AU  - Dimas, Kostantinos
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6046
AB  - Resistance to chemotherapeutic agents represents a major issue in anticancer therapy.
Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its aggressive behavior and
resistance to treatment. Alterations in the PI3K/AKT/mTOR pathway and/or high expression
of ATP binding cassette transporters, such as P-glycoprotein and breast cancer resistance
protein (BCRP), are frequently linked to chemo-resistance. Autophagy is a key player in the
metabolic and therapeutic stress response and represents a potential target for anticancer
therapy. Autophagy induction in response to chemotherapeutics may contribute to both
drug efficacy as well as drug resistance. We assessed the therapeutic efficacy of dual mTOR
kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX) in combination in ATC cells. Rhocell line was generated from parental human thyroid carcinoma 8505C via the selection of cells with a low accumulation of rhodamine 123 (P-glycoprotein and BCRP substrate). Rhocells were 10-fold more resistant to PTX compared to 8505C cells and more tumorigenic. Both vistusertib and PTX induced autophagosome formation in the investigated cell lines. In combination, vistusertib sensitized Rho- cells to PTX via autophagy induction and proliferation inhibition, indicating a synergistic effect between the two compounds. Additionally, vistusertib and PTX combination in Rho- and 8505C cells inhibited cell migration
and invasion in vitro. Furthermore, vistusertib and PTX combination effectively suppressed
tumor growth of ATC xenografts in immunodeficient NSG mice in vivo. Considering chemoresistance and high invasive properties of ATC, described combined approach could be useful for the design of novel targeted treatment strategies in this malignancy
PB  - COST Action CA1513
C3  - Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria
T1  - Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma
SP  - 30
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6046
ER  - 

@conference{
author = "Nešović, Marija and Milošević, Zorica and Banković, Jasna and Tsimplouli, Chrisiida and Sereti, Evangelia and Dragoj, Miodrag and Podolski-Renić, Ana and Stanković, Tijana and Jovanović, Mirna and Dimas, Kostantinos and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Resistance to chemotherapeutic agents represents a major issue in anticancer therapy.
Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its aggressive behavior and
resistance to treatment. Alterations in the PI3K/AKT/mTOR pathway and/or high expression
of ATP binding cassette transporters, such as P-glycoprotein and breast cancer resistance
protein (BCRP), are frequently linked to chemo-resistance. Autophagy is a key player in the
metabolic and therapeutic stress response and represents a potential target for anticancer
therapy. Autophagy induction in response to chemotherapeutics may contribute to both
drug efficacy as well as drug resistance. We assessed the therapeutic efficacy of dual mTOR
kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX) in combination in ATC cells. Rhocell line was generated from parental human thyroid carcinoma 8505C via the selection of cells with a low accumulation of rhodamine 123 (P-glycoprotein and BCRP substrate). Rhocells were 10-fold more resistant to PTX compared to 8505C cells and more tumorigenic. Both vistusertib and PTX induced autophagosome formation in the investigated cell lines. In combination, vistusertib sensitized Rho- cells to PTX via autophagy induction and proliferation inhibition, indicating a synergistic effect between the two compounds. Additionally, vistusertib and PTX combination in Rho- and 8505C cells inhibited cell migration
and invasion in vitro. Furthermore, vistusertib and PTX combination effectively suppressed
tumor growth of ATC xenografts in immunodeficient NSG mice in vivo. Considering chemoresistance and high invasive properties of ATC, described combined approach could be useful for the design of novel targeted treatment strategies in this malignancy",
publisher = "COST Action CA1513",
journal = "Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria",
title = "Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma",
pages = "30",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6046"
}

Nešović, M., Milošević, Z., Banković, J., Tsimplouli, C., Sereti, E., Dragoj, M., Podolski-Renić, A., Stanković, T., Jovanović, M., Dimas, K., Pešić, M.,& Dinić, J.. (2019). Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma. in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria
COST Action CA1513., 30.
https://hdl.handle.net/21.15107/rcub_ibiss_6046

Nešović M, Milošević Z, Banković J, Tsimplouli C, Sereti E, Dragoj M, Podolski-Renić A, Stanković T, Jovanović M, Dimas K, Pešić M, Dinić J. Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma. in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria. 2019;:30.
https://hdl.handle.net/21.15107/rcub_ibiss_6046 .

Nešović, Marija, Milošević, Zorica, Banković, Jasna, Tsimplouli, Chrisiida, Sereti, Evangelia, Dragoj, Miodrag, Podolski-Renić, Ana, Stanković, Tijana, Jovanović, Mirna, Dimas, Kostantinos, Pešić, Milica, Dinić, Jelena, "Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma" in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria (2019):30,
https://hdl.handle.net/21.15107/rcub_ibiss_6046 .

TY  - JOUR
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Dinić, Jelena
AU  - Tsimplouli, Chrisiida
AU  - Sereti, Evangelia
AU  - Dragoj, Miodrag
AU  - Paunović, Verica
AU  - Milovanović, Zorka
AU  - Stepanović, Marija
AU  - Tanić, Nikola
AU  - Dimas, Kostantinos
AU  - Pešić, Milica
PY  - 2018
UR  - http://link.springer.com/10.1007/s13402-018-0380-x
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3128
AB  - PURPOSE Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate. METHODS Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. RESULTS Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth. CONCLUSIONS Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.
T2  - Cellular Oncology (Dordrecht)
T1  - Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.
IS  - 4
VL  - 41
DO  - 10.1007/s13402-018-0380-x
SP  - 409
EP  - 426
ER  - 

@article{
author = "Milošević, Zorica and Banković, Jasna and Dinić, Jelena and Tsimplouli, Chrisiida and Sereti, Evangelia and Dragoj, Miodrag and Paunović, Verica and Milovanović, Zorka and Stepanović, Marija and Tanić, Nikola and Dimas, Kostantinos and Pešić, Milica",
year = "2018",
abstract = "PURPOSE Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate. METHODS Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. RESULTS Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth. CONCLUSIONS Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.",
journal = "Cellular Oncology (Dordrecht)",
title = "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.",
number = "4",
volume = "41",
doi = "10.1007/s13402-018-0380-x",
pages = "409-426"
}

Milošević, Z., Banković, J., Dinić, J., Tsimplouli, C., Sereti, E., Dragoj, M., Paunović, V., Milovanović, Z., Stepanović, M., Tanić, N., Dimas, K.,& Pešić, M.. (2018). Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.. in Cellular Oncology (Dordrecht), 41(4), 409-426.
https://doi.org/10.1007/s13402-018-0380-x

Milošević Z, Banković J, Dinić J, Tsimplouli C, Sereti E, Dragoj M, Paunović V, Milovanović Z, Stepanović M, Tanić N, Dimas K, Pešić M. Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.. in Cellular Oncology (Dordrecht). 2018;41(4):409-426.
doi:10.1007/s13402-018-0380-x .

Milošević, Zorica, Banković, Jasna, Dinić, Jelena, Tsimplouli, Chrisiida, Sereti, Evangelia, Dragoj, Miodrag, Paunović, Verica, Milovanović, Zorka, Stepanović, Marija, Tanić, Nikola, Dimas, Kostantinos, Pešić, Milica, "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma." in Cellular Oncology (Dordrecht), 41, no. 4 (2018):409-426,
https://doi.org/10.1007/s13402-018-0380-x . .

TY  - JOUR
AU  - Dragoj, Miodrag
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Tanić, Nikola
AU  - Pešić, Milica
AU  - Stanković, Tijana
PY  - 2017
UR  - http://link.springer.com/10.1007/s13402-016-0304-6
UR  - https://www.scopus.com/record/display.uri?eid=2-s2.0-84994434560&origin=SingleRecordEmailAlert&txGid=6CE299281CDB840158BFAC52EC5A2E1C.wsnAw8kcdt7IPYLO0V48gA:31
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2540
AB  - Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells. Methods: qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment. Results: We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion. Conclusions: From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.
T2  - Cellular Oncology
T1  - Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma
IS  - 1
VL  - 40
DO  - 10.1007/s13402-016-0304-6
SP  - 47
EP  - 62
ER  - 

@article{
author = "Dragoj, Miodrag and Milošević, Zorica and Banković, Jasna and Tanić, Nikola and Pešić, Milica and Stanković, Tijana",
year = "2017",
abstract = "Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells. Methods: qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment. Results: We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion. Conclusions: From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.",
journal = "Cellular Oncology",
title = "Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma",
number = "1",
volume = "40",
doi = "10.1007/s13402-016-0304-6",
pages = "47-62"
}

Dragoj, M., Milošević, Z., Banković, J., Tanić, N., Pešić, M.,& Stanković, T.. (2017). Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma. in Cellular Oncology, 40(1), 47-62.
https://doi.org/10.1007/s13402-016-0304-6

Dragoj M, Milošević Z, Banković J, Tanić N, Pešić M, Stanković T. Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma. in Cellular Oncology. 2017;40(1):47-62.
doi:10.1007/s13402-016-0304-6 .

Dragoj, Miodrag, Milošević, Zorica, Banković, Jasna, Tanić, Nikola, Pešić, Milica, Stanković, Tijana, "Targeting CXCR4 and FAK reverses doxorubicin resistance and suppresses invasion in non-small cell lung carcinoma" in Cellular Oncology, 40, no. 1 (2017):47-62,
https://doi.org/10.1007/s13402-016-0304-6 . .

TY  - JOUR
AU  - Podolski-Renić, Ana
AU  - Milošević, Zorica
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Banković, Jasna Z.
AU  - Pešić, Milica
PY  - 2016
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4051
AB  - Cancer-initiating cells referred to as cancer stem cells (CSCs) retain the essential property of self-renewal and protection. The protective mechanisms enable tumour regrowth even after the application of chemotherapy that was believed to be successful. Among the protective mechanisms of CSCs, the overexpression of ATP binding cassette (ABC) membrane transporters is highly important. ABC transporters involved in the development of cancer multidrug resistance (MDR) such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are considered as particular features of CSCs. They provide a shield for CSCs and protect them from the adverse effects of chemotherapeutics. Hence, combating MDR would be one of the strategies for the elimination of CSCs. In order to investigate this phenomenon many model systems comprising MDR cancer cells have been established. Some of them were developed by a selection process through exposure to various anticancer drugs, others by transfection of genes for ABC transporters, while some were obtained by sorting the side population considered to possess stemness and resistant phenotypes. Herein we review the potential of cancer MDR models for studying CSCs because gaining a better insight into the mechanisms of CSC resistance to chemotherapy may lead to the discovery of new therapeutic targets and the development of better anticancer strategies.
PB  - The Royal Society of Chemistry
T2  - MedChemComm
T1  - Mutual regulation and targeting of multidrug resistance and cancer stem phenotype
IS  - 12
VL  - 7
DO  - 10.1039/C6MD00391E
SP  - 2265
EP  - 2281
ER  - 

@article{
author = "Podolski-Renić, Ana and Milošević, Zorica and Dinić, Jelena and Stanković, Tijana and Banković, Jasna Z. and Pešić, Milica",
year = "2016",
abstract = "Cancer-initiating cells referred to as cancer stem cells (CSCs) retain the essential property of self-renewal and protection. The protective mechanisms enable tumour regrowth even after the application of chemotherapy that was believed to be successful. Among the protective mechanisms of CSCs, the overexpression of ATP binding cassette (ABC) membrane transporters is highly important. ABC transporters involved in the development of cancer multidrug resistance (MDR) such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are considered as particular features of CSCs. They provide a shield for CSCs and protect them from the adverse effects of chemotherapeutics. Hence, combating MDR would be one of the strategies for the elimination of CSCs. In order to investigate this phenomenon many model systems comprising MDR cancer cells have been established. Some of them were developed by a selection process through exposure to various anticancer drugs, others by transfection of genes for ABC transporters, while some were obtained by sorting the side population considered to possess stemness and resistant phenotypes. Herein we review the potential of cancer MDR models for studying CSCs because gaining a better insight into the mechanisms of CSC resistance to chemotherapy may lead to the discovery of new therapeutic targets and the development of better anticancer strategies.",
publisher = "The Royal Society of Chemistry",
journal = "MedChemComm",
title = "Mutual regulation and targeting of multidrug resistance and cancer stem phenotype",
number = "12",
volume = "7",
doi = "10.1039/C6MD00391E",
pages = "2265-2281"
}

Podolski-Renić, A., Milošević, Z., Dinić, J., Stanković, T., Banković, J. Z.,& Pešić, M.. (2016). Mutual regulation and targeting of multidrug resistance and cancer stem phenotype. in MedChemComm
The Royal Society of Chemistry., 7(12), 2265-2281.
https://doi.org/10.1039/C6MD00391E

Podolski-Renić A, Milošević Z, Dinić J, Stanković T, Banković JZ, Pešić M. Mutual regulation and targeting of multidrug resistance and cancer stem phenotype. in MedChemComm. 2016;7(12):2265-2281.
doi:10.1039/C6MD00391E .

Podolski-Renić, Ana, Milošević, Zorica, Dinić, Jelena, Stanković, Tijana, Banković, Jasna Z., Pešić, Milica, "Mutual regulation and targeting of multidrug resistance and cancer stem phenotype" in MedChemComm, 7, no. 12 (2016):2265-2281,
https://doi.org/10.1039/C6MD00391E . .

TY  - JOUR
AU  - Podolski-Renić, Ana
AU  - Milošević, Zorica
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Banković, Jasna
AU  - Pešić, Milica
PY  - 2016
UR  - http://xlink.rsc.org/?DOI=C6MD00391E
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2493
AB  - Cancer-initiating cells referred to as cancer stem cells (CSCs) retain the essential property of self-renewal and protection. The protective mechanisms enable tumour regrowth even after the application of chemotherapy that was believed to be successful. Among the protective mechanisms of CSCs, the overexpression of ATP binding cassette (ABC) membrane transporters is highly important. ABC transporters involved in the development of cancer multidrug resistance (MDR) such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are considered as particular features of CSCs. They provide a shield for CSCs and protect them from the adverse effects of chemotherapeutics. Hence, combating MDR would be one of the strategies for the elimination of CSCs. In order to investigate this phenomenon many model systems comprising MDR cancer cells have been established. Some of them were developed by a selection process through exposure to various anticancer drugs, others by transfection of genes for ABC transporters, while some were obtained by sorting the side population considered to possess stemness and resistant phenotypes. Herein we review the potential of cancer MDR models for studying CSCs because gaining a better insight into the mechanisms of CSC resistance to chemotherapy may lead to the discovery of new therapeutic targets and the development of better anticancer strategies.
T2  - MedChemComm
T1  - Mutual regulation and targeting of multidrug resistance and cancer stem phenotype
IS  - 12
VL  - 7
DO  - 10.1039/C6MD00391E
SP  - 2265
EP  - 2281
ER  - 

@article{
author = "Podolski-Renić, Ana and Milošević, Zorica and Dinić, Jelena and Stanković, Tijana and Banković, Jasna and Pešić, Milica",
year = "2016",
abstract = "Cancer-initiating cells referred to as cancer stem cells (CSCs) retain the essential property of self-renewal and protection. The protective mechanisms enable tumour regrowth even after the application of chemotherapy that was believed to be successful. Among the protective mechanisms of CSCs, the overexpression of ATP binding cassette (ABC) membrane transporters is highly important. ABC transporters involved in the development of cancer multidrug resistance (MDR) such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are considered as particular features of CSCs. They provide a shield for CSCs and protect them from the adverse effects of chemotherapeutics. Hence, combating MDR would be one of the strategies for the elimination of CSCs. In order to investigate this phenomenon many model systems comprising MDR cancer cells have been established. Some of them were developed by a selection process through exposure to various anticancer drugs, others by transfection of genes for ABC transporters, while some were obtained by sorting the side population considered to possess stemness and resistant phenotypes. Herein we review the potential of cancer MDR models for studying CSCs because gaining a better insight into the mechanisms of CSC resistance to chemotherapy may lead to the discovery of new therapeutic targets and the development of better anticancer strategies.",
journal = "MedChemComm",
title = "Mutual regulation and targeting of multidrug resistance and cancer stem phenotype",
number = "12",
volume = "7",
doi = "10.1039/C6MD00391E",
pages = "2265-2281"
}

Podolski-Renić, A., Milošević, Z., Dinić, J., Stanković, T., Banković, J.,& Pešić, M.. (2016). Mutual regulation and targeting of multidrug resistance and cancer stem phenotype. in MedChemComm, 7(12), 2265-2281.
https://doi.org/10.1039/C6MD00391E

Podolski-Renić A, Milošević Z, Dinić J, Stanković T, Banković J, Pešić M. Mutual regulation and targeting of multidrug resistance and cancer stem phenotype. in MedChemComm. 2016;7(12):2265-2281.
doi:10.1039/C6MD00391E .

Podolski-Renić, Ana, Milošević, Zorica, Dinić, Jelena, Stanković, Tijana, Banković, Jasna, Pešić, Milica, "Mutual regulation and targeting of multidrug resistance and cancer stem phenotype" in MedChemComm, 7, no. 12 (2016):2265-2281,
https://doi.org/10.1039/C6MD00391E . .

TY  - THES
AU  - Milošević, Zorica
PY  - 2014
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=2847
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:11053/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1024938162
UR  - http://nardus.mpn.gov.rs/123456789/5283
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2399
AB  - Kаrcinomi štitаste žlezde su nаjčešći mаligniteti endokrinog sistemа.
Klаsifikаcijа ovih mаlignitetа je izvršenа nа osnovu njihovih histopаtoloških
kаrаkteristikа nа pаpilаrni, folikulаrni medulаrni i аnаplаstični kаrcinom (ATC).
Većinа karcinoma štitаste žlezde je dobro diferencirаnа i imа odličnu prognozu
(pаpilаrni i folikulаrni), dok аnаplаstični kаrcinom predstаvljа аgresivni tip sа izrаzito
lošom prognozom uprkos rаzličitim terаpijskim pristupimа u njegovom lečenju.
Promene u PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnim putevima su
karakteristične za nastanak karcinoma štitaste žlezde, koji su urođeno rezistentni na
klasičnu hemioterapiju. Upravo promene u аktivnosti PI3K/AKT/mTOR i
RAS/MAPK/ERK signаlnih putevа mogu dovesti i do rezistencije nа klаsične
hemioterаpeutike. Još jedan od mogućih uzroka neuspehа hemioterаpije je i pojаvа
višestruke (engl. multi-drug, MDR) rezistencije. Najčešći uzrok MDR-a je povišena
ekspresija P-gp i BCRP transportnih pumpi.
Cilj ove studije je bio ispitivanje uloge ključnih komponenti
PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnih putevа u pаtogenezi i rezistenciji
ATC. Analizirane su promene na genskom i proteinskom nivou u uzorcima pаcijenаtа
obolelih od ovog tipa kаrcinomа, kao i efekat inhibicije komponenti signalnih puteva
kod humanih ATC ćelijskih linija. Pored toga, ispitana je i uloga P-gp i BCRP pumpi
u rezistenciji ATC.
Pokazano je da su i PI3K/AKT/mTOR i RAS/MAPK/ERK signаlni putevi
važni za genezu ATC, kao i da se pritom međusobno isključuju. NRAS onkogen i p53
tumor supresor su izmenjeni u ispitivanim tumorskim uzorcima sa visokom
učestalošću. Najčešće je izmenjen NRAS gen što ukazuje na njegovu ključnu ulogu u
razvoju ATC. Sve otkrivene mutacije u NRAS genu i dve mutacije u p53 genu su po
prvi put prijavljene kod ATC.
In vitro studije su pokazale da se inhibicijom komponenti RAS/MAPK/ERK i
PI3K/AKT/mTOR signalnih puteva povećava senzitivnost humanih ATC ćelija na
klasičnu hemioterapiju. Najefikasnijim se pokazao dvostruki mTOR inhibitor
AZD2014, kako u pojedinačnim tretmanima tako i u kombinaciji sa paklitakselom
(PTX) i doksorubicinom (DOX).
Imunohistohemijska analiza P-gp i BCRP pumpi pokazala je njihovo značajno
prisustvo kod ATC pacijenata što ukazuje na učešće ovih proteina u rezistenciji ATC.
Sortiranjem ATC ćelija sa smanjenom akumulacijom rodamina 123 (Rho123),
poznatog P-gp supstrata, uspostavljena je nova ATC ćelijska linija. Na taj način,
dobijen je model koji više odgovara fenotipu uočenom kod ATC pacijenata nego
komercijalne ATC ćelijske linije korišćene u ovoj studiji.. Na ovom modelu je
ispitana efikasnost kombinovanog tretmanadvostrukim mTOR inhibitorom AZD2014
i PTX-om. Pokazano je da AZD2014 ne samo da povećava osetljivost ATC ćelija na
PTX, već u kombinaciji sa ovim citostatikom efikasno inhibira i migraciju i invaziju
ATC ćelija. Imajući u vidu da su rezistentnost i invazivnost ATC glavni uzroci loše
prognoze, terapija kombinacijom dvostrukog mTOR inhibitora i PTX-a bi mogla
doprineti efikasnijem lečenju pacijenata obolelih od ovog karcinoma.
AB  - Thyroid carcinoma is the most common malignancy of the endocrine system.
Thyroid malignancies are classified according to their histopathological characteristic
as papillary, follicular, medullary and anaplastic thyroid carcinoma (ATC). Most
thyroid malignancies (papillary thyroid carcinoma and follicular thyroid carcinoma)
are well differentiated and have favorable prognosis. On the other hand, ATC is one
of the most aggressive human cancers, with an intrinsic resistance and dismal
prognosis despite various therapeutic modalities. Changes in components of
RAS/MAPK/ERK and PI3K/AKT/mTORpathways are common in thyroid cancer
genesis which are resistant to classic chemotherapy agents. Changes in the activity of
RAS/MAPK/ERK and PI3K/AKT/mTORsignaling pathways can lead to drug
resistance. Besides these changes, possible cause of chemotherapy resistance is also
multi-drug resistance (MDR). The most common cause of MDR is high expression of
P-gp and BCRP proteins.
The aim of this study was to investigate the role of the key components of
RAS/MAPK/ERK and PI3K/AKT/mTOR pathways in the pathogenesis and
chemoresistance of ATC. We analyzed gene and protein changes in set of ATC
patient samples. We also investigated the role of inhibition of RAS/MAPK/ERK and
PI3K/AKT/mTOR pathways in ATC chemosensitization using human ATC cell lines.
The role of P-gp and BCRP proteins in ATC chemoresistance was also investigated.
Analysis of alterations in RAS/MAPK/ERK and PI3K/AKT/mTOR pathways
in ATC patients indicated that both pathways cooperate in the development of ATC.
Our results revealed a negative correlation between the activity of RAS/MAPK/ERK
and PI3K/AKT/mTOR pathways in the samples of ATC patients. NRAS oncogene and
p53 tumor suppressor are mutated with high frequency in our set of ATC samples.
NRAS is dominantly mutated gene, indicating the importance of this gene in ATC
development. All detected mutations in NRAS gene, and two mutations in p53 gene,
have never been reported in ATC genesis before.
In vitro results suggest that the inhibition of either RAS/MAPK/ERK or
PI3K/AKT/mTOR components may confer sensitivity of ATC cells to classic
chemotherapeutics. Treatment with dual mTOR inhibitor, AZD2014, alone or in
combination with paclitaxel (PTX) or doxorubicin (DOX) was shown to be the most
effective.
Immunohistochemical analysis showed high P-gp and BCRP expression in
our ATC samples, which indicates the role of these proteins in ATC chemoresistance.
We sorted ATC cells with the low Rhodamin123 (Rho123) accumulation which is
substrate of P-gp protein and established new ATC cell line. In this way we obtained
in vitro model system more similar to the patients’ phenotype, then comercial ATC
cell lines used in this study. We investigated the potential of dual mTOR inhibitor,
AZD2014 combined with PTX to sensitize this new ATC cell line. It was showed that
treatment with AZD2014 not only sensitizes ATC cells to PTX, but also combined
with this cytostatic, efficiently inhibits ATC cell migration and invasion. Taking into
account that chemoresistance and invasiveness of ATC are the main causes of poor
outcome, the application of dual mTOR inhibitor combined with PTX, seems to be a
logical therapeutic strategy for patients with ATC.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju
T1  - The role of mTOR and MAPK signaling pathways in resistance of thyroid carcinoma to chemotherapy.
SP  - 1
EP  - 122
UR  - https://hdl.handle.net/21.15107/rcub_nardus_5283
ER  - 

@phdthesis{
author = "Milošević, Zorica",
year = "2014",
abstract = "Kаrcinomi štitаste žlezde su nаjčešći mаligniteti endokrinog sistemа.
Klаsifikаcijа ovih mаlignitetа je izvršenа nа osnovu njihovih histopаtoloških
kаrаkteristikа nа pаpilаrni, folikulаrni medulаrni i аnаplаstični kаrcinom (ATC).
Većinа karcinoma štitаste žlezde je dobro diferencirаnа i imа odličnu prognozu
(pаpilаrni i folikulаrni), dok аnаplаstični kаrcinom predstаvljа аgresivni tip sа izrаzito
lošom prognozom uprkos rаzličitim terаpijskim pristupimа u njegovom lečenju.
Promene u PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnim putevima su
karakteristične za nastanak karcinoma štitaste žlezde, koji su urođeno rezistentni na
klasičnu hemioterapiju. Upravo promene u аktivnosti PI3K/AKT/mTOR i
RAS/MAPK/ERK signаlnih putevа mogu dovesti i do rezistencije nа klаsične
hemioterаpeutike. Još jedan od mogućih uzroka neuspehа hemioterаpije je i pojаvа
višestruke (engl. multi-drug, MDR) rezistencije. Najčešći uzrok MDR-a je povišena
ekspresija P-gp i BCRP transportnih pumpi.
Cilj ove studije je bio ispitivanje uloge ključnih komponenti
PI3K/AKT/mTOR i RAS/MAPK/ERK signаlnih putevа u pаtogenezi i rezistenciji
ATC. Analizirane su promene na genskom i proteinskom nivou u uzorcima pаcijenаtа
obolelih od ovog tipa kаrcinomа, kao i efekat inhibicije komponenti signalnih puteva
kod humanih ATC ćelijskih linija. Pored toga, ispitana je i uloga P-gp i BCRP pumpi
u rezistenciji ATC.
Pokazano je da su i PI3K/AKT/mTOR i RAS/MAPK/ERK signаlni putevi
važni za genezu ATC, kao i da se pritom međusobno isključuju. NRAS onkogen i p53
tumor supresor su izmenjeni u ispitivanim tumorskim uzorcima sa visokom
učestalošću. Najčešće je izmenjen NRAS gen što ukazuje na njegovu ključnu ulogu u
razvoju ATC. Sve otkrivene mutacije u NRAS genu i dve mutacije u p53 genu su po
prvi put prijavljene kod ATC.
In vitro studije su pokazale da se inhibicijom komponenti RAS/MAPK/ERK i
PI3K/AKT/mTOR signalnih puteva povećava senzitivnost humanih ATC ćelija na
klasičnu hemioterapiju. Najefikasnijim se pokazao dvostruki mTOR inhibitor
AZD2014, kako u pojedinačnim tretmanima tako i u kombinaciji sa paklitakselom
(PTX) i doksorubicinom (DOX).
Imunohistohemijska analiza P-gp i BCRP pumpi pokazala je njihovo značajno
prisustvo kod ATC pacijenata što ukazuje na učešće ovih proteina u rezistenciji ATC.
Sortiranjem ATC ćelija sa smanjenom akumulacijom rodamina 123 (Rho123),
poznatog P-gp supstrata, uspostavljena je nova ATC ćelijska linija. Na taj način,
dobijen je model koji više odgovara fenotipu uočenom kod ATC pacijenata nego
komercijalne ATC ćelijske linije korišćene u ovoj studiji.. Na ovom modelu je
ispitana efikasnost kombinovanog tretmanadvostrukim mTOR inhibitorom AZD2014
i PTX-om. Pokazano je da AZD2014 ne samo da povećava osetljivost ATC ćelija na
PTX, već u kombinaciji sa ovim citostatikom efikasno inhibira i migraciju i invaziju
ATC ćelija. Imajući u vidu da su rezistentnost i invazivnost ATC glavni uzroci loše
prognoze, terapija kombinacijom dvostrukog mTOR inhibitora i PTX-a bi mogla
doprineti efikasnijem lečenju pacijenata obolelih od ovog karcinoma., Thyroid carcinoma is the most common malignancy of the endocrine system.
Thyroid malignancies are classified according to their histopathological characteristic
as papillary, follicular, medullary and anaplastic thyroid carcinoma (ATC). Most
thyroid malignancies (papillary thyroid carcinoma and follicular thyroid carcinoma)
are well differentiated and have favorable prognosis. On the other hand, ATC is one
of the most aggressive human cancers, with an intrinsic resistance and dismal
prognosis despite various therapeutic modalities. Changes in components of
RAS/MAPK/ERK and PI3K/AKT/mTORpathways are common in thyroid cancer
genesis which are resistant to classic chemotherapy agents. Changes in the activity of
RAS/MAPK/ERK and PI3K/AKT/mTORsignaling pathways can lead to drug
resistance. Besides these changes, possible cause of chemotherapy resistance is also
multi-drug resistance (MDR). The most common cause of MDR is high expression of
P-gp and BCRP proteins.
The aim of this study was to investigate the role of the key components of
RAS/MAPK/ERK and PI3K/AKT/mTOR pathways in the pathogenesis and
chemoresistance of ATC. We analyzed gene and protein changes in set of ATC
patient samples. We also investigated the role of inhibition of RAS/MAPK/ERK and
PI3K/AKT/mTOR pathways in ATC chemosensitization using human ATC cell lines.
The role of P-gp and BCRP proteins in ATC chemoresistance was also investigated.
Analysis of alterations in RAS/MAPK/ERK and PI3K/AKT/mTOR pathways
in ATC patients indicated that both pathways cooperate in the development of ATC.
Our results revealed a negative correlation between the activity of RAS/MAPK/ERK
and PI3K/AKT/mTOR pathways in the samples of ATC patients. NRAS oncogene and
p53 tumor suppressor are mutated with high frequency in our set of ATC samples.
NRAS is dominantly mutated gene, indicating the importance of this gene in ATC
development. All detected mutations in NRAS gene, and two mutations in p53 gene,
have never been reported in ATC genesis before.
In vitro results suggest that the inhibition of either RAS/MAPK/ERK or
PI3K/AKT/mTOR components may confer sensitivity of ATC cells to classic
chemotherapeutics. Treatment with dual mTOR inhibitor, AZD2014, alone or in
combination with paclitaxel (PTX) or doxorubicin (DOX) was shown to be the most
effective.
Immunohistochemical analysis showed high P-gp and BCRP expression in
our ATC samples, which indicates the role of these proteins in ATC chemoresistance.
We sorted ATC cells with the low Rhodamin123 (Rho123) accumulation which is
substrate of P-gp protein and established new ATC cell line. In this way we obtained
in vitro model system more similar to the patients’ phenotype, then comercial ATC
cell lines used in this study. We investigated the potential of dual mTOR inhibitor,
AZD2014 combined with PTX to sensitize this new ATC cell line. It was showed that
treatment with AZD2014 not only sensitizes ATC cells to PTX, but also combined
with this cytostatic, efficiently inhibits ATC cell migration and invasion. Taking into
account that chemoresistance and invasiveness of ATC are the main causes of poor
outcome, the application of dual mTOR inhibitor combined with PTX, seems to be a
logical therapeutic strategy for patients with ATC.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju, The role of mTOR and MAPK signaling pathways in resistance of thyroid carcinoma to chemotherapy.",
pages = "1-122",
url = "https://hdl.handle.net/21.15107/rcub_nardus_5283"
}

Milošević, Z.. (2014). Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-122.
https://hdl.handle.net/21.15107/rcub_nardus_5283

Milošević Z. Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju. in University of Belgrade, Faculty of Biology. 2014;:1-122.
https://hdl.handle.net/21.15107/rcub_nardus_5283 .

Milošević, Zorica, "Uloga mTOR i MAPK signalnih puteva u rezistenciji karcinoma štitaste žlezde na hemioterapiju" in University of Belgrade, Faculty of Biology (2014):1-122,
https://hdl.handle.net/21.15107/rcub_nardus_5283 .