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CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition
  1. Yen-Yun Wang, PhD*,
  2. Pei-Wen Hsieh, PhD,,
  3. Yuk-Kwan Chen, DDS, MS§,,
  4. Stephen Chu-Sung Hu, MD, PhD#,**,
  5. Ya-Ling Hsu, MS*,
  6. Chun-Hao Tsai, MS, and
  7. Shyng-Shiou F. Yuan, MD, PhD*,††,‡‡,§§
  1. * Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung;
  2. Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University;
  3. Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan;
  4. § Division of Oral Pathology and Maxillofacial Radiology, Kaohsiung Medical University Hospital;
  5. School of Dentistry, College of Dental Medicine, Kaohsiung Medical University;
  6. Oral and Maxillofacial Imaging Center, College of Dental Medicine, Kaohsiung Medical University;
  7. # Department of Dermatology, College of Medicine, Kaohsiung Medical University;
  8. ** Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University;
  9. †† Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University;
  10. ‡‡ Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University; and
  11. §§ Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  1. Address correspondence and reprint requests to Shyng-Shiou F. Yuan, MD, PhD, Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. E-mail: yuanssf{at}kmu.edu.tw.

Abstract

Objective The β-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of β-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a β-nitrostyrene derivative CYT-Rx20 (3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated.

Methods The effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, β-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo.

Results CYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers β-catenin and Twist.

Conclusions CYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.

  • β-Nitrostyrene
  • ROS
  • DNA damage
  • Apoptosis
  • Migration
  • Cervical cancer

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Footnotes

  • The authors declare that there are no conflicts of interest.