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Updated: May 28, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Characterisation and manipulation of docetaxel resistant prostate cancer cell lines
Amanda J O'Neill1, Maria Prencipe, Catherine Dowling
1UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. amanda.oneill@ucd.ie
Background:
There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.
Results:
The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel.
Conclusion:
This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.
Insights
Investigating Docetaxel resistance in prostate cancer revealed multiple mechanisms. Nuclear factor-kappa B (NF-κB) activation is a key driver of resistance, offering a potential therapeutic target for advanced disease.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Advanced castration-resistant prostate cancer lacks effective treatments.
- Docetaxel (Taxotere®) offers limited survival benefit due to drug resistance.
- Understanding Docetaxel resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Docetaxel resistance in prostate cancer.
- To identify potential therapeutic targets for overcoming Docetaxel resistance.
Main Methods:
- Generation and characterization of Docetaxel-resistant prostate cancer cell lines (DU-145 R, 22RV1 R, PC-3 R).
- Analysis of P-glycoprotein expression and function.
- Assessment of cellular senescence and autophagy.
- Evaluation of pro- and anti-apoptotic gene/protein expression.
- Measurement of nuclear factor-kappa B (NF-κB) activity and IκB phosphorylation.
- Inhibition of NF-κB using BAY 11-7082.
Main Results:
- P-glycoprotein mediated Docetaxel resistance in DU-145 R and 22RV1 R cells, reversed by Elacridar.
- PC-3 resistant cells showed no resistance mediated by senescence or autophagy, but exhibited altered apoptotic gene/protein expression.
- Docetaxel induced increased NF-κB activity and IκB phosphorylation in PC-3 cells, which was reversed by NF-κB inhibition.
Conclusions:
- Multiple mechanisms contribute to Docetaxel resistance in prostate cancer.
- Nuclear factor-kappa B (NF-κB) plays a critical role in mediating Docetaxel resistance.
- NF-κB represents a promising therapeutic target for overcoming Docetaxel resistance in advanced prostate cancer.
