Platycodin D induces apoptosis in human prostate carcinoma cells via ROS-dependent inactivation of the PI3K/AKT/mTOR signaling pathway

Background: Platycodin D is a triterpene saponin present in Platycodi Radix, an herbal medicine used for treating various diseases. Recently, this saponin has been identified as a bioactive natural compound with health benefits, including anticancer properties and no side effects. However, studies on its anticancer effects in human prostate cancer (PCa) cells remain limited. In this study, we elucidated the mechanism of anticancer activity of platycodin D in human PCa cells. Methods: After measuring the cytotoxicity of platycodin D, the anticancer potential of this compound was determined by analyzing the induction of apoptotic cell death, DNA damage, reactive oxygen species (ROS) generation, glutathione content, caspase activity and mitochondrial membrane potential (MMP). Additionally, the underlying mechanism of platycodin D-induced apoptosis was determined through various analyses including protein expression analysis. Results: Platycodin D treatment induced apoptosis in PCa cells by activating the caspase cascade and reducing the protein expression levels of the inhibitor of the apoptosis family. In addition, platycodin D disrupted mitochondrial integrity by altering Bcl-2 family protein expression and MMP levels, leading to increased cytochrome c release into the cytosol. Moreover, platycodin D suppressed the pro-survival phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PAM) pathway. Pretreatment with a PI3K inhibitor significantly enhanced the cytotoxic effect of platycodin D on PC-3 cells. Furthermore, platycodin D promoted the generation of ROS, while ROS scavengers restored reduced cell viability by attenuating DNA damage and apoptosis through inhibition of platycodin D-mediated inactivation of the PAM pathway. Platycodin D induces apoptosis in PC-3 cells via ROS-dependent inactivation of the PAM pathway, suggesting that ROS generation plays a key role as an early mediator of platycodin D-mediated anticancer effects. Conclusions: Our findings indicate that platycodin D may serve as a potential candidate for inhibiting human PCa cell proliferation.