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Targeting Foxm1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer
  1. Gina L. Westhoff, MD*,
  2. Yi Chen, MD, PhD and
  3. Nelson N.H. Teng, MD, PhD
  1. *Division of Gynecologic Oncology, Legacy Health, Portland, OR; and
  2. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA.
  1. Address correspondence and reprint requests to Nelson N. H. Teng, MD, PhD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology Stanford Cancer Institute Stanford University, 300 Pasteur Dr, HH333 Stanford, CA 94305. E-mail: teng@stanford.edu.

Abstract

Objective Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo.

Methods Human ovarian cancer cell lines and patients’ ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets.

Results Ovarian cancer cell lines and the patients’ ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients’ ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients’ ascites cells ex vivo.

Conclusion Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.

  • Drug combination
  • FOXM1
  • Ovarian cancer
  • Platinum resistant
  • Thiostrepton

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Footnotes

  • The authors declare no conflicts of interest.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

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