Redox-active nitroxides enhance cisplatin efficacy against cervical cancer

Cisplatin remains the primary treatment for most cervical cancer cases, though its clinical efficacy is hindered by dose-dependent toxicity and incurring chemoresistance. The overexpression of the glucocorticoid receptor (GR) and cellular redox state is linked to increased resistance to chemotherapy in cervical cancer. This study explores the combinations of novel steroidal and nitroxide-based treatments to improve the efficacy of cisplatin against cervical cancer. Two lead nitroxide-functionalised prednisolone hybrids (CS91 and CS187) were identified for their potent anti-proliferative activity in multiple cervical squamous cell carcinoma (SCC) cell lines. These compounds exhibit comparable anti-proliferative activity to the parent nitroxides, while maintaining GR binding capability. When combined with cisplatin, CS91 and CS187 induced a dose-dependent reduction in cell viability across multiple cervical cancer cell lines, which was optimised to preserve above 80 % healthy cell viability but decrease cancer cell viability below 15 %. Mechanistic studies revealed that these compounds raised intracellular reactive oxygen species (ROS) levels, with further enhancement in combination with cisplatin. This combination approach was found to be synergistic, resulting in decreased glutathione (GSH) levels and increased DNA damage compared to cisplatin alone. In summary, nitroxide-based hybrids exhibit potent anti-proliferative effects and potentiate cisplatin efficacy through ROS-mediated mechanisms, offering a promising targeted strategy for cervical cancer treatment.