Overcoming cisplatin resistance in ovarian cancer: A novel approach via mitochondrial targeting peptide Pal-pHK-pKV.

Cisplatin (DDP) resistance in advanced stages of ovarian cancer significantly reduces survival rates. Mitochondria may serve as a potential therapeutic target for ovarian cancer. Pal-pHK-pKV is a mitochondrial targeting peptide synthesized by supramolecular assembly. Our study aims to investigate whether Pal-pHK-pKV serves as a useful strategy to reverse DDP resistance in ovarian cancer. Subcutaneous tumor implantation of the DDP-resistant ovarian cancer cell line A2780CP was conducted in nude mice, and drugs were administered intraperitoneally to compare the inhibitory effects of Pal-pHK-pKV and DDP on A2780CP cells in vivo. Combination index values were calculated for various concentrations of DDP and Pal-pHK-pKV to determine the optimal combination concentration. Mitochondrial membrane potential, cytochrome C distribution and immunofluorescence were also measured. Our studies demonstrated that Pal-pHK-pKV treatment reduced the proliferation, invasion and metastasis of ovarian cancer cells and impaired mitochondrial function. Furthermore, the combination of Pal-pHK-pKV and DDP exhibited a synergistic effect. Mechanistically, Pal-pHK-pKV can impair mitochondrial function, reduce mitochondrial membrane potential and release ROS. On the other hand, Pal-pHK-pKV can affect ERK pathway activation and inhibit tumor development. In conclusion, the mitochondria-specific amphiphilic peptide Pal-pHK-pKV provides a novel approach for treating ovarian cancer and may potentially overcome DDP drug resistance.