Polyphyllin <scp>VII</scp> Enhances the Sensitivity of Prostate Cancer Cells to Docetaxel by Promoting Mitochondrial Dysfunction and Inducing Ferroptosis

Docetaxel (DTX) is the preferred chemotherapeutic drug for prostate cancer (Pca), but the emergence of resistance has significantly reduced its efficacy. Polyphyllin VII (PPVII), a small molecule natural product derived from the traditional herb Paris polyphylla, has shown anticancer potential. This study aims to investigate the effects and mechanisms of PPVII combined with DTX in treating Pca. DTX-sensitive DU-145 cells and DTX-resistant DU145/DTX cells were utilized for experiments in this study. Cell viability was assessed using MTT assays, while apoptosis, cell cycles, and ferroptosis were analyzed through flow cytometry and Western blot. Mitochondrial function was evaluated using immunofluorescence. Additionally, the expression of proteins related to the AMP-activated protein kinase/mammalian target of the rapamycin/S6 kinase (AMPK/mTOR/S6K) signaling pathway was also examined to further investigate the underlying mechanisms. PPVII significantly enhanced the inhibitory effect of DTX, reduced cell viability (p < 0.05), and promoted apoptosis (p < 0.05) and cell cycle arrest (p < 0.05). Specifically, PPVII increased the sensitivity of Pca cells to DTX by inducing ferroptosis and affecting mitochondrial function. Notably, the activation of the AMPK/mTOR/S6K signaling pathway played a crucial role in this process. This study revealed the synergistic effects and potential mechanisms of PPVII combined with DTX in Pca cells, and provided a reference for effectively overcoming DTX resistance in the clinical treatment of Pca.