Association between the apoptotic effect of Cabazitaxel and its pro-oxidant efficacy on the redox adaptation...

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Redox adaptation confers resistance to oxidative stress in cancer cells.
• Prostate cancer (PC) cells with redox adaptation exhibit reduced sensitivity to Cabazitaxel (Cab), a key drug for metastatic castration-resistant PC (mCRPC).

Purpose of the Study:

• To investigate the association between Cabazitaxel's apoptotic and pro-oxidant effects and redox adaptation in PC cells with varying phenotypes.
• To explore the role of redox adaptation in modulating drug sensitivity and survival pathways in prostate cancer.

Main Methods:

• Utilized LNCaP (mPC), LNCaP-HPR (oxidative stress-resistant mPC), C4-2 (mCRPC), and RWPE-1 (normal prostate epithelial) cells.
• Assessed Cabazitaxel's effects on reactive oxygen species (ROS) generation, mitochondrial damage, and key redox-sensitive proteins (p-Nrf2, HIF-1α, p-NF-κB).
• Evaluated cytotoxic and apoptotic effects of Cabazitaxel across different cell lines.

Main Results:

• Cabazitaxel demonstrated pro-oxidant and apoptotic effects proportional to its efficacy, more pronounced in less aggressive LNCaP cells.
• Reduced pro-oxidant and apoptotic effects were observed in redox-adapted LNCaP-HPR and C4-2 cells, indicating decreased drug sensitivity.
• Cabazitaxel increased p-NF-κB activation in aggressive PC cells, suggesting a role in survival under increased ROS.
• RWPE-1 cells showed less sensitivity to Cabazitaxel's cytotoxic effects compared to LNCaP, but exhibited altered pro-oxidant responses.

Conclusions:

• Cabazitaxel's efficacy is variable and influenced by cellular redox adaptation and phenotype.
• Altered regulation of redox adaptation in aggressive PC cells diminishes Cabazitaxel's pro-oxidant and apoptotic impact.
• Targeting redox-sensitive proteins and pathways could enhance Cabazitaxel's therapeutic effect in advanced prostate cancer.