Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma
2018
Аутори:
Milošević, ZoricaBanković, Jasna
Dinić, Jelena
Tsimplouli, Chrisiida
Sereti, Evangelia
Dragoj, Miodrag
Paunović, Verica
Milovanović, Zorka
Nešović, Marija
Tanić, Nikola
Dimas, Kostantinos
Pešić, Milica
Тип документа:
Чланак у часопису (Рецензирана верзија)
,
© 2020 Springer Nature Switzerland AG
Метаподаци
Приказ свих података о документуАпстракт:
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.
Напомена:
This is the peer reviewed version of the following article: 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. Cell Oncol (Dordr). 2018;41(4):409–26. http://dx.doi.org/10.1007/s13402-018-0380-x.
Related to: https://radar.ibiss.bg.ac.rs/handle/123456789/3128.
Кључне речи:
AZD2014; Anaplastic thyroid carcinoma; Chemo-resistance; Paclitaxel; Targeted therapy; mTORИзвор:
Cellular Oncology (Dordrecht), 2018, 41, 409-426Финансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- COST Action CM1106 (Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells)
- COST Action CM1407 (Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery)
DOI: 10.1007/s13402-018-0380-x
ISSN: 2211-3428
PubMed: 29790111
WoS: 000442467200006
Scopus: 2-s2.0-85051861484
URI
https://link.springer.com/article/10.1007%2Fs13402-018-0380-xhttps://radar.ibiss.bg.ac.rs/123456789/3887