Back to Search Start Over

Src Inhibition Can Synergize with Gemcitabine and Reverse Resistance in Triple Negative Breast Cancer Cells via the AKT/c-Jun Pathway.

Authors :
Zhen-Hua Wu
Chen Lin
Ming-Ming Liu
Jian Zhang
Zhong-Hua Tao
Xi-Chun Hu
Source :
PLoS ONE, Vol 11, Iss 12, p e0169230 (2016)
Publication Year :
2016
Publisher :
Public Library of Science (PLoS), 2016.

Abstract

Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells.By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway.In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
11
Issue :
12
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.95acb24780bb4629ae1b2855a8ea93ce
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0169230