Open Access

ARTICLE

Picropodophyllotoxin: A Natural Epimer Targeting STAT3 Phosphorylation and ROS-Mediated Apoptosis in Oral Squamous Cell Carcinoma Cells

Jung-Il Chae^1,#, Ji-Hye Seo^1,#, Goo Yoon², Young-Joo Jeon^3,*, Woo-Keun Kim^4,*

1 Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju, 54896, Republic of Korea
2 Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan, 58554, Republic of Korea
3 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
4 Biosystem Research Group, Department of Predictive Model Research Center, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea

* Corresponding Authors: Young-Joo Jeon. Email: ; Woo-Keun Kim. Email:
# These authors contributed equally: Jung-Il Chae and Ji-Hye Seo

(This article belongs to the Special Issue: Molecular Mechanisms of Natural Compounds in Cell Signaling and Cancer Therapy)

BIOCELL 2025, 49(4), 647-663. https://doi.org/10.32604/biocell.2025.062137

Received 11 December 2024; Accepted 28 March 2025; Issue published 30 April 2025

Abstract

Background: Picropodophllotoxin (PPT), a principal component of Podophyllum hexandrum root, demonstrates various beneficial biological activities in multiple cancer types, including antitumor and antiproliferative properties. Despite its known effects, the specific mechanisms by which PPT induces apoptosis in oral squamous cell carcinoma (OSCC) cells lack full clarification. Aims: This study aimed to evaluate the role of PPT in inducing apoptosis in OSCC cells by targeting signal transducer and activator of transcription 3 (STAT3) and to investigate the underlying molecular pathways. Methods: Human OSCC cell lines (HN22 and HSC4) were treated with PPT. Cell viability, colony formation, and apoptotic morphological changes were evaluated. Reactive oxygen species (ROS) generation and mitochondrial function were assessed using tetramethyl rhodamine methyl ester, MitoSOX, and 2^′, 7^′-dichlorodihydrofluorescein diacetate (DCFH-DA) assays following PPT treatment. The expression of apoptosis markers, including cleaved Poly (ADP-Ribose) Polymerase (c-PARP) and other target proteins, was measured using western blotting. ROS involvement was further confirmed using the ROS scavenger N-acetylcysteine (NAC). Results: Treatment with PPT resulted in a substantial reduction in cell viability, a decrease in colony formation capacity, and evident morphological changes in OSCC cells. These effects were dose- and time-dependent, as evidenced by increased expression of c-PARP. PPT-induced apoptosis was mediated by excessive ROS generation, which was almost completely blocked by NAC pretreatment. Conclusions: These findings suggest that PPT may serve as a promising therapeutic agent for treating human oral cancer by inhibiting the STAT3 pathway and inducing ROS-mediated apoptosis.

---

Keywords

---