Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.143
Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling
Seung-On Lee1,†, Sang Hoon Joo2,†, Ah-Won Kwak3, Mee-Hyun Lee4, Ji-Hye Seo5, Seung-Sik Cho3, Goo Yoon3, Jung-Il Chae5,* and Jung-Hyun Shim1,3,6,*
1Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554,
2College of Pharmacy, Daegu Catholic University, Gyeongsan 38430,
3Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554,
4College of Korean Medicine, Dongshin University, Naju 58245,
5Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
6The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
*E-mail: s1004jh@gmail.com (Shim JH), jichae@jbnu.ac.kr (Chae JI)
Tel: +82-61-450-2684 (Shim JH), +82-63-270-4024 (Chae JI)
Fax: +82-61-450-2689 (Shim JH), +82-63-270-4037 (Chae JI)
The first two authors contributed equally to this work.
Received: August 31, 2021; Revised: September 9, 2021; Accepted: September 10, 2021; Published online: October 13, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Podophyllotoxin, Colon cancer, Cell cycle arrest, Reactive oxygen species, p38, Apoptosis


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