2. Academic Validation
  3. Triggering mitotic catastrophe by podophyllotoxin induces apoptosis in oral squamous cell carcinoma

Triggering mitotic catastrophe by podophyllotoxin induces apoptosis in oral squamous cell carcinoma

  • Arch Oral Biol. 2025 Nov:179:106396. doi: 10.1016/j.archoralbio.2025.106396.
Su-Jung Choi 1,  Ji-Hoon Kim 2,  Hyun-Ji Kim 1,  Dong-Guk Park 1,  Bohwan Jin 3,  Won Woo Lee 3,  Kyoung-Ok Hong 1,  Sak Lee 1,  Thantrira Porntaveetus 4,  Jae-Jin Cho 5,  Seong-Doo Hong 1,  Sung-Dae Cho 6
Affiliations

Affiliations

  • 1 Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea.
  • 2 Department of Pathology, Duke University School of Medicine, DUMC 3712, Durham, NC 27710, United States.
  • 3 Laboratory Animal Center, CHA University, CHA Biocomplex, Sampyeong-dong, Seongnam 13488, Republic of Korea.
  • 4 Center of Excellent in Precision Dentistry and Digital Health, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
  • 5 Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea; Department of Dental Regenerative Biotechnology School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea.
  • 6 Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: efiwdsc@snu.ac.kr.
PMID: 40966849 DOI: 10.1016/j.archoralbio.2025.106396
Abstract

Objective: This study investigated the relationship between mitotic catastrophe (MC) and Apoptosis in oral squamous cell carcinoma (OSCC) using podophyllotoxin (PPT), a natural compound with antimitotic properties.

Design: We evaluated the concentration-dependent effects of PPT on cell proliferation (CCK-8 and soft agar assays) and morphology (transmission electron microscopy). Mechanistic insights were obtained by assessing DNA damage (western blotting), cell cycle progression (sub-G1 analysis), and apoptosis-related protein activation in both 2D and 3D spheroid models of HSC-3 oral squamous carcinoma cells.

Results: PPT exerted pronounced inhibitory effects on cell proliferation and anchorage-independent growth accompanied by morphological indications of MC, such as enlarged multinucleated cells. DNA damage induced by PPT resulted in ataxia telangiectasia mutated kinase and checkpoint kinase 2 activation, leading to G2/M arrest and cyclin B1upregulation. Importantly, PPT-induced MC was followed by Apoptosis, as evidenced by an increased sub-G1 population, Annexin V positivity, and Caspase activation. Mitochondrial dysfunction, as indicated by altered membrane potential and enhanced Bax expression, underscored the apoptotic process. Caspase-2 activation emerged as a pivotal event, cleaving Bid and establishing a link between MC and the intrinsic apoptotic pathway. The effects were consistent across both 2D and 3D models, suggesting a robust therapeutic potential.

Conclusions: This study provides compelling evidence supporting the potential therapeutic significance of inducing MC-mediated Apoptosis in OSCC. The results underscore the role of PPT and its derivatives, such as etoposide and teniposide, in targeting rapidly dividing Cancer cells through interference with mitotic progression, offering insights into novel therapeutic strategies for oral Cancer.

Keywords

Apoptosis; Caspase-2; DNA damage; Healthcare; Mitotic catastrophe; Oral squamous cell carcinoma; Podophyllotoxin.

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