Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling

  • Lee, Seung-On (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University) ;
  • Joo, Sang Hoon (College of Pharmacy, Daegu Catholic University) ;
  • Kwak, Ah-Won (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Lee, Mee-Hyun (College of Korean Medicine, Dongshin University) ;
  • Seo, Ji-Hye (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University) ;
  • Cho, Seung-Sik (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Yoon, Goo (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Chae, Jung-Il (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University) ;
  • Shim, Jung-Hyun (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University)
  • Received : 2021.08.31
  • Accepted : 2021.09.10
  • Published : 2021.11.01
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Abstract

Podophyllotoxin (PT), a lignan compound from the roots and rhizomes of Podophyllum peltatum, has diverse pharmacological activities including anticancer effect in several types of cancer. The molecular mechanism of the anticancer effects of PT on colorectal cancer cells has not been reported yet. In this study, we sought to evaluate the anticancer effect of PT on human colorectal cancer HCT116 cells and identify the detailed molecular mechanism. PT inhibited the growth of cells and colony formation in a concentration-dependent manner and induced apoptosis as determined by the annexin V/7-aminoactinomycin D double staining assay. PT-induced apoptosis was accompanied by cell cycle arrest in the G2/M phase and an increase in the generation of reactive oxygen species (ROS). The effects of PT on the induction of ROS and apoptosis were prevented by pretreatment with N-acetyl-L-cysteine (NAC), indicating that an increase in ROS generation mediates the apoptosis of HCT116 cells induced by PT. Furthermore, Western blot analysis showed that PT upregulated the level of phospho (p)-p38 mitogen-activated protein kinase (MAPK). The treatment of SB203580, a p38 inhibitor, strongly prevented the apoptosis induced by PT, suggesting that PT-induced apoptosis involved the p38 MAPK signaling pathway. In addition, PT induced the loss of mitochondrial membrane potential and multi-caspase activation. The results suggested that PT induced cell cycle arrest in the G2/M phase and apoptosis through the p38 MAPK signaling pathway by upregulating ROS in HCT116 cells.

Keywords

Acknowledgement

We greatly appreciated using the Convergence Research Laboratory (established by the MNU Innovation Support Project in 2019) to conduct this research. This research was funded by the Basic Science Research Program of National Research Foundation Korea, grant number 2019R1A2C1005899.

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