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

Abstract

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 of Podophyllum hexandrum root 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.

• Authors: Ah-Won Kwak, Goo Yoon, Mee-Hyun Lee, Seung-Sik Cho, Jung-Hyun Shim, Jung-Il Chae
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 13 (Jun 30 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32629820 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• Reactive Oxygen Species
• picropodophyllin
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 8
• p38 Mitogen-Activated Protein Kinases
• Podophyllotoxin

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Esophageal Neoplasms (pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy, metabolism, pathology)
• Humans
• Isomerism
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (metabolism)
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Podophyllotoxin (analogs & derivatives, metabolism, pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)