Antiviral Drug 2-thio-6-azauridine Sensitizes Paclitaxel-Resistant Triple Negative Breast Cancer Cells by Targeting Mammosphere Formation and ABC Transporters

Abstract

Background: 2-thio-6-azauridine (TAU) is a nucleoside analog and potential antiviral drug. The antiproliferative activity of TAU has been evaluated in limited cancer cell lines. The present study is aimed to evaluate the effect of TAU on drug sensitization mechanism in paclitaxel (PTX) resistant triple-negative breast cancer (TNBC) cells.Methods: The cell death mechanism was determined using MTT, BrdU incorporation, apoptosis, and DNA damage Western blot and RT-PCR assays. A specific ELISA method was used to determine the caspase-3 activity and expression levels of MRP1, MDR1, BCRP, and MRP8. Western blot analysis was used to assess the expression of CD151, MRP1, MDR1, and BCRP in CD151 overexpressing PTX-resistant TNBC cells.Results: The combination of TAU and PTX (10:20nM) synergistically inhibited the 50% viability of 12-fold PTX-resistant TNBC cells. Mechanistically, the combination inhibited the proliferation by arresting the cell cycle at the G2M phase and induced apoptosis by altering cell integrity and nuclear morphology as well as damaging DNA. The combination sensitized the PTX-resistant TNBC cells by increasing BAX and decreasing Bcl-2 expression, activating caspase-3, and reducing the expression of ABC transporters MRP1 and MDR1. The combination reduced the expression of MRP1 and MDR1 in CD151 overexpressing PTX-resistant TNBC cells, indicating the role of CD151in TAU mediated sensitization of PTX-resistant TNBC cells. The combination also reduced the mammosphere formation efficiency of PTX-resistant TNBC cells. Conclusion: Overall, the present study illustrated the promising ability of TAU in sensitizing drug-resistant TNBC cells to PTX.