Redox-active nitroxides enhance cisplatin efficacy against cervical cancer

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Cisplatin is a primary cervical cancer treatment, but its efficacy is limited by toxicity and chemoresistance.
• Glucocorticoid receptor (GR) overexpression and altered cellular redox state contribute to cervical cancer chemoresistance.

Purpose of the Study:

• To explore novel steroidal and nitroxide-based treatments combined with cisplatin to overcome chemoresistance in cervical cancer.
• To identify compounds that improve cisplatin efficacy while minimizing toxicity.

Main Methods:

• Synthesized and identified two lead nitroxide-functionalised prednisolone hybrids (CS91 and CS187).
• Assessed anti-proliferative activity and GR binding capability of CS91 and CS187.
• Evaluated the efficacy of CS91 and CS187 in combination with cisplatin against cervical cancer cell lines.
• Investigated the underlying mechanisms, including reactive oxygen species (ROS), glutathione (GSH) levels, and DNA damage.

Main Results:

• CS91 and CS187 demonstrated potent anti-proliferative activity in cervical squamous cell carcinoma (SCC) lines, comparable to parent nitroxides, while retaining GR binding.
• Combinations of CS91/CS187 with cisplatin significantly reduced cancer cell viability (<15%) while preserving healthy cell viability (>80%).
• The combination therapy synergistically increased intracellular ROS levels, decreased GSH levels, and enhanced DNA damage compared to cisplatin alone.

Conclusions:

• Nitroxide-based hybrids (CS91, CS187) show potent anti-proliferative effects against cervical cancer.
• These hybrids potentiate cisplatin efficacy through ROS-mediated mechanisms, representing a promising targeted strategy for cervical cancer treatment.