A Novel Wogonin Derivative Induces Apoptosis in PC-3M Cells by Targeting Mitochondrial Dysfunction and Activating the ROS-p38/MAPK Pathway

Current cancer treatments have significant limitations. Designing TPP+-modified, mitochondrial-targeted drugs can improve anticancer efficacy. Although wogonin exhibits antitumor activity, it has drawbacks, including poor solubility and limited distribution. This study designed and synthesized 27 derivatives, including nine novel wogonin triphenylphosphine derivatives that demonstrated in vitro antitumor activity. Mito-WO-8, one of these derivatives, exhibited potent activity against PC-3M cells (IC50 = 3.19 μmol/L), demonstrating 15-fold higher potency than wogonin. Further analysis revealed that Mito-WO-8 accumulates more in mitochondria than wogonin and induces mitochondrial dysfunction, including increased reactive oxygen species, reduced membrane potential, and activation of the MPTP channel. Transcriptome and network analyses revealed that Mito-WO-8 activates the p38/MAPK pathway. Downregulation of p-MKK6 and p-p38, as well as upregulation of DDIT3 and cleaved caspase-3, were validated by Western blot (WB) and quantitative polymerase chain reaction (qPCR). Therefore, Mito-WO-8 enhances mitochondrial enrichment and induces mitochondrial damage. This process is associated with apoptosis and the activation of the ROS-p38/MAPK pathway. Additionally, the study found that Mito-WO-8 exhibits a stronger binding affinity for mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2) than the parent compound (−9.6 kJ/mol vs. −6.6 kJ/mol), suggesting a potential interaction with GPD2. This finding establishes a foundation for further investigation into its targeted antitumor mechanism.