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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Co-treatment by docetaxel and vinblastine breaks down P-glycoprotein mediated chemo-resistance
Mahsa Mohseni1, Nasser Samadi2, Parisa Ghanbari1
1Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Objectives:
Chemoresistance remains the main causes of treatment failure and mortality in cancer patients. There is an urgent need to investigate novel approaches to improve current therapeutic modalities and increase cancer patients' survival. Induction of drug efflux due to overexpression of P-glycoproteins is considered as an important leading cause of multidrug resistance. In this study, we investigated the role of combination treatments of docetaxel and vinblastine in overcoming P-glycoprotein mediated inhibition of apoptosis and induction of cell proliferation in human non-small cell lung carcinoma cells.
Materials And Methods:
Cell proliferation and apoptosis were assessed using MTT assay and DAPI staining, respectively. P-glycoprotein expression was evaluated in gene and protein levels by Real-time RT-PCR and Western blot analysis, respectively.
Results:
Combination treatment of the cells with docetaxel and vinblastine decreased the IC50 values for docetaxel from (30±3.1) to (15±2.6) nM and for vinblastine from (30±5.9) to (5±5.6) nM (P≤0.05). P-glycoprotein mRNA expression level showed a significant up-regulation in the cells incubated with each drug alone (P≤0.001). Incubation of the cells with combined concentrations of both agents neutralized P-glycoprotein overexpression (P≤0.05). Adding verapamil, a P-glycoprotein inhibitor caused a further increase in the percentage of apoptotic cells when the cells were treated with both agents.
Conclusion:
Our results suggest that combination therapy along with P-glycoprotein inhibition can be considered as a novel approach to improve the efficacy of chemotherapeutics in cancer patients with high P-glycoprotein expression.
Insights
Combination chemotherapy with docetaxel and vinblastine can overcome P-glycoprotein mediated drug resistance in non-small cell lung cancer. This approach neutralizes P-glycoprotein overexpression, enhancing therapeutic efficacy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Chemoresistance is a major cause of cancer treatment failure and mortality.
- P-glycoprotein (P-gp) overexpression leads to multidrug resistance by increasing drug efflux.
- Novel strategies are needed to improve chemotherapy effectiveness in cancer patients.
Purpose of the Study:
- To investigate the efficacy of combining docetaxel and vinblastine in overcoming P-gp-mediated chemoresistance.
- To evaluate the impact of combination therapy on apoptosis and cell proliferation in non-small cell lung cancer (NSCLC) cells.
- To assess the effect of combination treatment on P-glycoprotein expression levels.
Main Methods:
- Cell proliferation was measured using MTT assay.
- Apoptosis was quantified by DAPI staining.
- P-glycoprotein gene and protein expression were analyzed via Real-time RT-PCR and Western blot, respectively.
Main Results:
- Combination therapy significantly reduced IC50 values for both docetaxel and vinblastine.
- Single-agent treatment upregulated P-glycoprotein mRNA, while combination therapy neutralized this overexpression.
- Co-treatment with verapamil (a P-gp inhibitor) further increased apoptosis.
Conclusions:
- Combination therapy with docetaxel and vinblastine shows promise in overcoming P-gp-mediated chemoresistance.
- This approach can enhance the efficacy of chemotherapeutics in NSCLC patients with high P-gp expression.
- Targeting P-glycoprotein in combination with chemotherapy offers a novel therapeutic strategy.
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