Picropodophyllotoxin, an Epimer of Podophyllotoxin, Causes Apoptosis of Human Esophageal Squamous Cell Carcinoma Cells Through ROS-Mediated JNK/P38 MAPK Pathways

Esophageal squamous cell carcinoma (ESCC), a major histologic type of esophageal cancer, is one of the frequent causes of cancer-related death worldwide. Picropodophyllotoxin (PPT) is the main component ofPodophyllum hexandrumroot with antitumor activity via apoptosis-mediated mechanisms in several cancer cells. However, the underlying mechanism of the PPT effects in apoptosis induction in cancer remains ambiguous. Hence, in this study, we evaluate the anti-cancer effects of PPT in apoptotic signaling pathway-related mechanisms in ESCC cells. First, to verify the effect of PPT on ESCC cell viability, we employed an MTT assay. PPT inhibited the viability of ESCC cells in time- and dose-dependent manners. PPT induced G2/M phase cell cycle arrest and annexin V-stained cell apoptosis through the activation of the c-Jun N-terminal kinase (JNK)/p38 pathways. Furthermore, the treatment of KYSE 30 and KYSE 450 ESCC cells with PPT induced apoptosis involving the regulation of endoplasmic reticulum stress- and apoptosis-related proteins by reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, and multi-caspase activation. In conclusion, our results indicate that the apoptotic effect of PPT on ESCC cells has the potential to become a new anti-cancer drug by increasing ROS levels and inducing the JNK/p38 signaling pathways.