2. Academic Validation
  3. Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest

Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest

  • Chem Biol Interact. 2024 Nov 1:403:111244. doi: 10.1016/j.cbi.2024.111244.
Chun-Yu Chen 1,  Yu-Zhen Ye 2,  Yu-Hao Huang 3,  Yew-Min Tzeng 4,  Ranal Gurbanov 5,  Wen-Ling Wang 6,  Wen-Wei Chang 7
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, 435403, Taiwan; Department of Nursing, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, 35664, Taiwan. Electronic address: yoyo116984@gmail.com.
  • 2 Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan. Electronic address: izanyeh881112@gmail.com.
  • 3 Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan.
  • 4 Department of Applied Science, National Taitung University, Sec. 2, University Rd., Taitung, 95092, Taiwan. Electronic address: ymtzeng@nttu.edu.tw.
  • 5 School of Medicine, Gazi University, Emniyet Mah., Bandırma Cad., No:6/1, 06560, Yenimahalle, Ankara, Turkey. Electronic address: ranalgurbanov@gmail.com.
  • 6 Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan. Electronic address: u8966003.lin@gmail.com.
  • 7 Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan. Electronic address: changww@csmu.edu.tw.
PMID: 39276908 DOI: 10.1016/j.cbi.2024.111244
Abstract

Endometrial Cancer (EC) is a common gynecological Cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows Anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and Cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased Reactive Oxygen Species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (Chk1) and 2 (Chk2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated Glutathione Peroxidase 1 (GPX1), an antioxidant Enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.

Keywords

DNA damage; Endometrial cancer; GPX1; Ovatodiolide; Reactive oxygen species.

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