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 . .