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Updated: Aug 15, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Comprehensive Evaluation of Multiple Approaches Targeting ABCB1 to Resensitize Docetaxel-Resistant Prostate Cancer
Dinah Linke1,2,3, Lukas Donix1,2,3, Claudia Peitzsch2,3,4,5
1Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Abstract:
Docetaxel (DTX) is a mainstay in the treatment of metastatic prostate cancer. Failure of DTX therapy is often associated with multidrug resistance caused by overexpression of efflux membrane transporters of the ABC family such as the glycoprotein ABCB1. This study investigated multiple approaches targeting ABCB1 to resensitize DTX-resistant (DTXR) prostate cancer cell lines. In DU145 DTXR and PC-3 DTXR cells as well as age-matched parental controls, the expression of selected ABC transporters was analyzed by quantitative PCR, Western blot, flow cytometry and immunofluorescence. ABCB1 effluxing activity was studied using the fluorescent ABCB1 substrate rhodamine 123. The influence of ABCB1 inhibitors (elacridar, tariquidar), ABCB1-specific siRNA and inhibition of post-translational glycosylation on DTX tolerance was assessed by cell viability and colony formation assays. In DTXR cells, only ABCB1 was highly upregulated, which was accompanied by a strong effluxing activity and additional post-translational glycosylation of ABCB1. Pharmacological inhibition and siRNA-mediated knockdown of ABCB1 completely resensitized DTXR cells to DTX. Inhibition of glycosylation with tunicamycin affected DTX resistance partially in DU145 DTXR cells, which was accompanied by a slight intracellular accumulation and decreased effluxing activity of ABCB1. In conclusion, DTX resistance can be reversed by various strategies with small molecule inhibitors representing the most promising and feasible approach.
Insights
Docetaxel resistance in prostate cancer is often due to ABCB1 transporter overexpression. Targeting ABCB1 with inhibitors or siRNA can resensitize resistant cells to docetaxel therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Docetaxel (DTX) is a key treatment for metastatic prostate cancer.
- Multidrug resistance, often mediated by ABCB1 transporter overexpression, limits DTX efficacy.
- Developing strategies to overcome DTX resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate methods for resensitizing docetaxel-resistant (DTXR) prostate cancer cell lines by targeting ABCB1.
- To analyze the expression and activity of ABCB1 in DTXR cells.
- To evaluate the impact of ABCB1 inhibition and other strategies on DTX resistance.
Main Methods:
- Quantitative PCR, Western blot, flow cytometry, and immunofluorescence were used to analyze ABC transporter expression.
- Rhodamine 123 was used to assess ABCB1 efflux activity.
- Cell viability and colony formation assays were performed to evaluate DTX tolerance after treatment with ABCB1 inhibitors, siRNA, or tunicamycin.
Main Results:
- DTXR cells showed significant upregulation of ABCB1 with increased efflux activity and post-translational glycosylation.
- Pharmacological inhibition and siRNA-mediated knockdown of ABCB1 completely restored DTX sensitivity in DTXR cells.
- Inhibition of glycosylation partially reversed DTX resistance, affecting ABCB1 activity.
Conclusions:
- Docetaxel resistance in prostate cancer is strongly associated with ABCB1 upregulation and activity.
- Targeting ABCB1 through pharmacological inhibition or siRNA is a highly effective strategy to overcome DTX resistance.
- Small molecule inhibitors targeting ABCB1 represent a promising and feasible approach for reversing docetaxel resistance.
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