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Title: Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters

Abstract

Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restoremore » full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to paclitaxel. • Paclitaxel resistance was associated with increased levels of ABCB1 and ABCC3 protein. • ABCB1 silencing increased significantly sensitivity to both paclitaxel and doxorubicin.« less

Authors:
Publication Date:
OSTI Identifier:
22690843
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 310; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 54 ENVIRONMENTAL SCIENCES; ABUNDANCE; APOPTOSIS; CELL PROLIFERATION; CONCENTRATION RATIO; DOXORUBICIN; MAMMARY GLANDS; MESSENGER-RNA; NEOPLASMS; PHENOTYPE; PROTEINS; SENSITIVITY

Citation Formats

Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. United States: N. p., 2016. Web. doi:10.1016/J.TAAP.2016.09.020.
Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@. Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. United States. doi:10.1016/J.TAAP.2016.09.020.
Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@. Tue . "Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters". United States. doi:10.1016/J.TAAP.2016.09.020.
@article{osti_22690843,
title = {Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters},
author = {Němcová-Fürstová, Vlasta, E-mail: vlasta.furstova@},
abstractNote = {Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100 nM and 300 nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype. Interestingly, resistance in both paclitaxel-resistant sublines is circumvented by the second-generation taxane SB-T-1216. Moreover, we demonstrated that it was not possible to establish sublines of SK-BR-3 and MCF-7 cells resistant to this taxane. It means that at least the tested breast cancer cells are unable to develop resistance to some taxanes. Employing mRNA expression profiling of all known human ABC transporters and subsequent Western blot analysis of the expression of selected transporters, we demonstrated that only the ABCB1/PgP and ABCC3/MRP3 proteins were up-regulated in both paclitaxel-resistant sublines. We found up-regulation of ABCG2/BCRP and ABCC4 proteins only in paclitaxel-resistant SK-BR-3 cells. In paclitaxel-resistant MCF-7 cells, ABCB4/MDR3 and ABCC2/MRP2 proteins were up-regulated. Silencing of ABCB1 expression using specific siRNA increased significantly, but did not completely restore full sensitivity to both paclitaxel and doxorubicin. Thus we showed a key, but not exclusive, role for ABCB1 in mechanisms of paclitaxel resistance. It suggests the involvement of multiple mechanisms in paclitaxel resistance in tested breast cancer cells. - Highlights: • Expression of all ABC transporters in paclitaxel-resistant sublines of SK-BR-3 and MCF-7 cells was analyzed. • SK-BR-3 and MCF-7 cells are unable to develop resistance to some taxanes. • Some taxanes are able to overcome developed resistance to paclitaxel. • Paclitaxel resistance was associated with increased levels of ABCB1 and ABCC3 protein. • ABCB1 silencing increased significantly sensitivity to both paclitaxel and doxorubicin.},
doi = {10.1016/J.TAAP.2016.09.020},
journal = {Toxicology and Applied Pharmacology},
number = ,
volume = 310,
place = {United States},
year = {Tue Nov 01 00:00:00 EDT 2016},
month = {Tue Nov 01 00:00:00 EDT 2016}
}