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Effects of Cabazitaxel in Renal Cell Carcinoma Cell Lines
Kosuke Mizutani1, Masashi Tomoda2, Yuta Ohno3
1Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan mizutech@gifu-u.ac.jp.
Background/Aim:
Advanced renal cell carcinoma is treated with mammalian target of rapamycin (mTOR) inhibitors or tyrosine kinase inhibitors (TKIs). The effects of these drugs are, however, limited and novel treatment strategies are required. Clear-cell type renal cell carcinoma (ccRCC) is chemo-resistant, in part, due to expression of multidrug resistance proteins such as p-glycoprotein. Cabazitaxel, a tubulin-binding taxane drug used for castration-resistant prostate cancer, has less affinity for p-glycoprotein compared to docetaxel. In the current study, the effects of docetaxel and cabazitaxel on ccRCC cells were investigated.
Materials And Methods:
The expression of p-glycoprotein was evaluated in the ccRCC cell lines, Caki-1, KMRC-1 and OS-RC-2 by western blotting. Cells were treated with cabazitaxel or docetaxel, and growth kinetics and tubulin polymerization were determined by the WST-1 assay and cell-based tubulin polymerization assay, respectively. Intracellular drug concentrations were measured by chromatography. AKT activation after treatment was examined by western blotting.
Results:
All ccRCC cell lines expressed p-glycoprotein. Cabazitaxel inhibited cell growth and induced tubulin polymerization more potently than docetaxel. The intracellular concentration of cabazitaxel was much higher than docetaxel in all cell lines. Both docetaxel and cabazitaxel inhibit AKT phosphorylation at 5 min among three cells.
Conclusion:
Cabazitaxel inhibits growth of ccRCC cells expressing p-glycoprotein and could thus be possibly used for advanced ccRCC patients in combination with targeted-therapy enhancing their effects.
Insights
Cabazitaxel effectively inhibits clear-cell renal cell carcinoma (ccRCC) growth by overcoming p-glycoprotein resistance. This taxane drug shows greater potency than docetaxel, offering a potential new treatment strategy for advanced ccRCC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Advanced renal cell carcinoma (RCC) treatment faces limitations with current mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs).
- Clear-cell renal cell carcinoma (ccRCC) exhibits chemo-resistance, partly due to p-glycoprotein expression, a multidrug resistance protein.
- Cabazitaxel, a taxane, demonstrates lower affinity for p-glycoprotein than docetaxel, suggesting potential efficacy in resistant ccRCC.
Purpose of the Study:
- To investigate the effects of cabazitaxel and docetaxel on ccRCC cells.
- To evaluate the potential of cabazitaxel as a treatment for p-glycoprotein-expressing ccRCC.
Main Methods:
- Western blotting to assess p-glycoprotein expression in ccRCC cell lines (Caki-1, KMRC-1, OS-RC-2).
- WST-1 assay and cell-based tubulin polymerization assay to determine growth kinetics and tubulin polymerization.
- Chromatography to measure intracellular drug concentrations and western blotting for AKT activation.
Main Results:
- All tested ccRCC cell lines expressed p-glycoprotein.
- Cabazitaxel demonstrated superior inhibition of cell growth and induction of tubulin polymerization compared to docetaxel.
- Intracellular cabazitaxel concentrations were significantly higher than docetaxel, and both drugs inhibited AKT phosphorylation.
Conclusions:
- Cabazitaxel effectively inhibits the growth of ccRCC cells that express p-glycoprotein.
- Cabazitaxel presents a promising therapeutic option for advanced ccRCC, potentially enhancing targeted therapy effects.
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