Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer

Yu Chieh Lee, Chii Hong Lee, Hsiang Ping Tsai, Herng Wei An, Chi-Ming Lee, Jen Chine Wu, Chien Shu Chen, Shih Hao Huang, Jaulang Hwang, Kur Ta Cheng, Phui Ly Leiw, Chi Long Chen, Chun Mao Lin

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Abstract

DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p <0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers.

Original languageEnglish
Article numbere0132579
JournalPLoS One
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 24 2015

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lee, Y. C., Lee, C. H., Tsai, H. P., An, H. W., Lee, C-M., Wu, J. C., Chen, C. S., Huang, S. H., Hwang, J., Cheng, K. T., Leiw, P. L., Chen, C. L., & Lin, C. M. (2015). Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer. PLoS One, 10(7), [e0132579]. https://doi.org/10.1371/journal.pone.0132579