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Basic Science
The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice
  1. Ikuko Sawada, MD,
  2. Kae Hashimoto, MD, PhD,
  3. Kenjiro Sawada, MD, PhD,
  4. Yasuto Kinose, MD, PhD,
  5. Koji Nakamura, MD,
  6. Aska Toda, MD,
  7. Erika Nakatsuka, MD,
  8. Akihiko Yoshimura, MD,
  9. Seiji Mabuchi, MD, PhD,
  10. Tomoyuki Fujikawa, PhD,
  11. Akiko Itai, PhD and
  12. Tadashi Kimura, MD, PhD
  1. * Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka; and
  2. † Institute of Medicinal Molecular Design, Inc, Bunkyo-ku, Tokyo, Japan.
  1. Address correspondence and reprint requests to Kae Hashimoto, MD, PhD, Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka Suita, Osaka 5650871, Japan. E-mail: kae.h{at}gyne.med.oska-u.ac.jp.

Abstract

Objective Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo.

Methods NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model.

Results The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation.

Conclusions IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the treatment of ovarian cancer.

  • Angiogenesis
  • IKKβ inhibitor
  • NF-κB
  • Ovarian cancer

https://doi.org/10.1097/IGC.0000000000000668

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    Footnotes

    • The authors declare no conflicts of interest.