Combined Arctigenin and Curcumin Treatment Induces Redox and Metabolic Stress, AMPK Phosphorylation, and Apoptotic...

Background/Objectives: Prostate cancer remains a major cause of cancer-related mortality in men. Arctigenin (ATG) and curcumin (CUR) exhibit anticancer activity; however, their combined effects on redox and metabolic stress remain incompletely understood. This study investigated the anticancer effects of combined ATG and CUR treatment in prostate cancer cells. Methods: PC-3 prostate cancer cells and normal human prostate epithelial (HPrEC) cells were treated with ATG and CUR alone or in combination. Cell viability, combination index, reactive oxygen species (ROS), GSH/GSSG ratio, ATP levels, AMPK phosphorylation, and apoptosis-related responses were evaluated. The contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC), and treatment effects were further assessed in three-dimensional (3D) spheroids. Results: Combined ATG and CUR treatment produced greater growth-inhibitory and apoptotic responses in PC-3 cells than in HPrEC cells and was synergistic under the tested condition in PC-3 cells. The combination increased ROS, reduced the GSH/GSSG ratio and ATP levels, increased AMPK phosphorylation, and enhanced apoptosis-related responses. NAC attenuated ROS accumulation, partially restored cell viability and ATP levels, and reduced caspase-3/7 activity in PC-3 cells. In 3D PC-3 spheroids, NAC also partially restored viability and ATP levels and attenuated increases in cleaved caspase-3 and cleaved PARP. Conclusions: Combined ATG and CUR treatment induces redox and metabolic stress and enhanced apoptotic responses in PC-3 cells, with weaker effects in HPrEC cells. NAC rescue supports a functional contribution of oxidative stress. These findings support an association between ROS-related metabolic stress, AMPK phosphorylation, and apoptotic signaling, while precise causal relationships require further investigation.